ID VHL_HUMAN Reviewed; 213 AA. AC P40337; B2RE45; Q13599; Q6PDA9; DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot. DT 15-DEC-1998, sequence version 2. DT 27-MAR-2024, entry version 249. DE RecName: Full=von Hippel-Lindau disease tumor suppressor; DE AltName: Full=Protein G7; DE AltName: Full=pVHL; GN Name=VHL; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), VARIANTS VHLD ILE-75 RP DEL AND 82-ARG--VAL-84 DEL, AND ALTERNATIVE SPLICING (ISOFORM 2). RX PubMed=8493574; DOI=10.1126/science.8493574; RA Latif F., Tory K., Gnarra J., Yao M., Duh F.-M., Orcutt M.L., RA Stackhouse T., Kuzmin I., Modi W., Geil L., Schmidt L., Zhou F., Li H., RA Wei M.H., Chen F., Glenn G., Choyke P., Walther M.M., Weng Y., RA Duan D.-S.R., Dean M., Glavac D., Richards F.M., Crossey P.A., RA Ferguson-Smith M.A., le Paslier D., Chumakov I., Cohen D., Chinault A.C., RA Maher E.R., Linehan W.M., Zbar B., Lerman M.I.; RT "Identification of the von Hippel-Lindau disease tumor suppressor gene."; RL Science 260:1317-1320(1993). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16641997; DOI=10.1038/nature04728; RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J., RA Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., RA Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A., RA Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L., RA Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G., RA Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W., RA Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., RA Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P., RA Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H., RA Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., RA Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., RA Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., RA Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., RA Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B., RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H., RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J., RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X., RA Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R., RA Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.; RT "The DNA sequence, annotation and analysis of human chromosome 3."; RL Nature 440:1194-1198(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT TYR-110. RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 33-67 AND 156-213, AND VARIANT RP PRO-163. RC TISSUE=Renal cell carcinoma; RA Wenzel M.; RL Submitted (APR-1996) to the EMBL/GenBank/DDBJ databases. RN [7] RP DEVELOPMENTAL STAGE, AND ALTERNATIVE SPLICING (ISOFORMS 1 AND 2). RX PubMed=8733131; DOI=10.1093/hmg/5.5.639; RA Richards F.M., Schofield P.N., Fleming S., Maher E.R.; RT "Expression of the von Hippel-Lindau disease tumour suppressor gene during RT human embryogenesis."; RL Hum. Mol. Genet. 5:639-644(1996). RN [8] RP INTERACTION WITH CUL2. RX PubMed=9122164; DOI=10.1073/pnas.94.6.2156; RA Pause A., Lee S., Worrel R., Chen D.Y.T., Burgess W.H., Linehan W.M., RA Klausner R.D.; RT "The von Hippel-Lindau tumor-suppressor gene product forms a stable complex RT with human CUL-2, a member of the Cdc53 family of proteins."; RL Proc. Natl. Acad. Sci. U.S.A. 94:2156-2161(1997). RN [9] RP ALTERNATIVE SPLICING (ISOFORM 3). RX PubMed=9671762; DOI=10.1073/pnas.95.15.8817; RA Schoenfeld A., Davidowitz E.J., Burk R.D.; RT "A second major native von Hippel-Lindau gene product, initiated from an RT internal translation start site, functions as a tumor suppressor."; RL Proc. Natl. Acad. Sci. U.S.A. 95:8817-8822(1998). RN [10] RP INTERACTION WITH ELONGIN BC COMPLEX. RX PubMed=7660130; DOI=10.1126/science.7660130; RA Kibel A., Iliopoulos O., DeCaprio J.A., Kaelin W.G. Jr.; RT "Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and RT C."; RL Science 269:1444-1446(1995). RN [11] RP FUNCTION (ISOFORM 3), AND SUBCELLULAR LOCATION (ISOFORMS 1 AND 3). RX PubMed=9751722; DOI=10.1073/pnas.95.20.11661; RA Iliopoulos O., Ohh M., Kaelin W.G. Jr.; RT "pVHL19 is a biologically active product of the von Hippel-Lindau gene RT arising from internal translation initiation."; RL Proc. Natl. Acad. Sci. U.S.A. 95:11661-11666(1998). RN [12] RP INTERACTION WITH CHAPERONES, AND VARIANT VHLD PRO-158. RX PubMed=10635329; DOI=10.1016/s1097-2765(00)80233-6; RA Feldman D.E., Thulasiraman V., Ferreyra R.G., Frydman J.; RT "Formation of the VHL-elongin BC tumor suppressor complex is mediated by RT the chaperonin TRiC."; RL Mol. Cell 4:1051-1061(1999). RN [13] RP INTERACTION WITH HIF1A, FUNCTION, CHARACTERIZATION OF VARIANT PHE-162, AND RP MUTAGENESIS OF TYR-98. RX PubMed=10944113; DOI=10.1093/emboj/19.16.4298; RA Tanimoto K., Makino Y., Pereira T., Poellinger L.; RT "Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von RT Hippel-Lindau tumor suppressor protein."; RL EMBO J. 19:4298-4309(2000). RN [14] RP IDENTIFICATION IN E3 UBIQUITIN-PROTEIN LIGASE COMPLEXES. RX PubMed=11384984; DOI=10.1074/jbc.m103093200; RA Kamura T., Burian D., Yan Q., Schmidt S.L., Lane W.S., Querido E., RA Branton P.E., Shilatifard A., Conaway R.C., Conaway J.W.; RT "Muf1, a novel elongin BC-interacting leucine-rich repeat protein that can RT assemble with Cul5 and Rbx1 to reconstitute a ubiquitin ligase."; RL J. Biol. Chem. 276:29748-29753(2001). RN [15] RP INTERACTION WITH HIF1AN; HIF1A AND HISTONE DEACETYLASES. RC TISSUE=Brain; RX PubMed=11641274; DOI=10.1101/gad.924501; RA Mahon P.C., Hirota K., Semenza G.L.; RT "FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate RT repression of HIF-1 transcriptional activity."; RL Genes Dev. 15:2675-2686(2001). RN [16] RP INTERACTION WITH USP33. RX PubMed=11739384; DOI=10.1074/jbc.m108269200; RA Li Z., Na X., Wang D., Schoen S.R., Messing E.M., Wu G.; RT "Ubiquitination of a novel deubiquitinating enzyme requires direct binding RT to von Hippel-Lindau tumor suppressor protein."; RL J. Biol. Chem. 277:4656-4662(2002). RN [17] RP INTERACTION WITH JADE1, AND SUBCELLULAR LOCATION. RX PubMed=12169691; DOI=10.1074/jbc.m205040200; RA Zhou M.I., Wang H., Ross J.J., Kuzmin I., Xu C., Cohen H.T.; RT "The von Hippel-Lindau tumor suppressor stabilizes novel plant homeodomain RT protein Jade-1."; RL J. Biol. Chem. 277:39887-39898(2002). RN [18] RP INTERACTION WITH RNF139. RX PubMed=12032852; DOI=10.1038/sj.onc.1205437; RA Gemmill R.M., Bemis L.T., Lee J.P., Sozen M.A., Baron A., Zeng C., RA Erickson P.F., Hooper J.E., Drabkin H.A.; RT "The TRC8 hereditary kidney cancer gene suppresses growth and functions RT with VHL in a common pathway."; RL Oncogene 21:3507-3516(2002). RN [19] RP INTERACTION WITH ALAS1. RX PubMed=16234850; DOI=10.1139/o05-045; RA Abu-Farha M., Niles J., Willmore W.G.; RT "Erythroid-specific 5-aminolevulinate synthase protein is stabilized by low RT oxygen and proteasomal inhibition."; RL Biochem. Cell Biol. 83:620-630(2005). RN [20] RP FUNCTION, AND INTERACTION WITH HIF1A. RX PubMed=17981124; DOI=10.1016/j.cell.2007.08.045; RA Cheng J., Kang X., Zhang S., Yeh E.T.H.; RT "SUMO-specific protease 1 is essential for stabilization of HIF1alpha RT during hypoxia."; RL Cell 131:584-595(2007). RN [21] RP INTERACTION WITH EPAS1. RX PubMed=19208626; DOI=10.1074/jbc.m808737200; RA Furlow P.W., Percy M.J., Sutherland S., Bierl C., McMullin M.F., RA Master S.R., Lappin T.R., Lee F.S.; RT "Erythrocytosis-associated HIF-2alpha mutations demonstrate a critical role RT for residues C-terminal to the hydroxylacceptor proline."; RL J. Biol. Chem. 284:9050-9058(2009). RN [22] RP INTERACTION WITH ADRB2, SUBCELLULAR LOCATION, AND FUNCTION. RX PubMed=19584355; DOI=10.1126/scisignal.2000444; RA Xie L., Xiao K., Whalen E.J., Forrester M.T., Freeman R.S., Fong G., RA Gygi S.P., Lefkowitz R.J., Stamler J.S.; RT "Oxygen-regulated beta(2)-adrenergic receptor hydroxylation by EGLN3 and RT ubiquitylation by pVHL."; RL Sci. Signal. 2:RA33-RA33(2009). RN [23] RP INTERACTION WITH LIMD1; AJUBA AND WTIP, AND IDENTIFICATION IN A COMPLEX RP WITH LIMD1; EGLN1/PHD2; ELOB AND CUL2. RX PubMed=22286099; DOI=10.1038/ncb2424; RA Foxler D.E., Bridge K.S., James V., Webb T.M., Mee M., Wong S.C., Feng Y., RA Constantin-Teodosiu D., Petursdottir T.E., Bjornsson J., Ingvarsson S., RA Ratcliffe P.J., Longmore G.D., Sharp T.V.; RT "The LIMD1 protein bridges an association between the prolyl hydroxylases RT and VHL to repress HIF-1 activity."; RL Nat. Cell Biol. 14:201-208(2012). RN [24] RP INTERACTION WITH DCUN1D1. RX PubMed=23401859; DOI=10.1128/mcb.01342-12; RA Heir P., Sufan R.I., Greer S.N., Poon B.P., Lee J.E., Ohh M.; RT "DCNL1 functions as a substrate sensor and activator of cullin 2-RING RT ligase."; RL Mol. Cell. Biol. 33:1621-1631(2013). RN [25] RP FUNCTION, PATHWAY, AND SUBCELLULAR LOCATION. RX PubMed=34290272; DOI=10.1038/s41598-021-94132-5; RA Ganner A., Gehrke C., Klein M., Thegtmeier L., Matulenski T., RA Wingendorf L., Wang L., Pilz F., Greidl L., Meid L., Kotsis F., Walz G., RA Frew I.J., Neumann-Haefelin E.; RT "VHL suppresses RAPTOR and inhibits mTORC1 signaling in clear cell renal RT cell carcinoma."; RL Sci. Rep. 11:14827-14827(2021). RN [26] RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 54-213 IN COMPLEX WITH 556-575 OF RP HIF1A; ELOB AND ELOC. RX PubMed=12004076; DOI=10.1126/science.1073440; RA Min J.-H., Yang H., Ivan M., Gertler F., Kaelin W.G. Jr., Pavletich N.P.; RT "Structure of an HIF-1alpha-pVHL complex: hydroxyproline recognition in RT signaling."; RL Science 296:1886-1889(2002). RN [27] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 52-213 IN COMPLEX WITH 549-582 OF RP HIF1A; 17-112 OF ELOB AND ELOC. RX PubMed=12050673; DOI=10.1038/nature00767; RA Hon W.-C., Wilson M.I., Harlos K., Claridge T.D.W., Schofield C.J., RA Pugh C.W., Maxwell P.H., Ratcliffe P.J., Stuart D.I., Jones E.Y.; RT "Structural basis for the recognition of hydroxyproline in HIF-1 alpha by RT pVHL."; RL Nature 417:975-978(2002). RN [28] RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 54-213 IN COMPLEX WITH 17-112 OF RP ELOB AND ELOC. RX PubMed=10205047; DOI=10.1126/science.284.5413.455; RA Stebbins C.E., Kaelin W.G. Jr., Pavletich N.P.; RT "Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor RT suppressor function."; RL Science 284:455-461(1999). RN [29] RP VARIANT HEMANGIOBLASTOMA PHE-135. RX PubMed=8069849; RA Kanno H., Kondo K., Ito S., Yamamoto I., Fujii S., Torigoe S., Sakai N., RA Hosaka M., Shuin T., Yao M.; RT "Somatic mutations of the von Hippel-Lindau tumor suppressor gene in RT sporadic central nervous system hemangioblastomas."; RL Cancer Res. 54:4845-4847(1994). RN [30] RP VARIANTS IN LUNG CANCER. RX PubMed=8183553; RA Sekido Y., Bader S., Latif F., Gnarra J.R., Gazdar A.F., Linehan W.M., RA Zbar B., Lerman M.I., Minna J.D.; RT "Molecular analysis of the von Hippel-Lindau disease tumor suppressor gene RT in human lung cancer cell lines."; RL Oncogene 9:1599-1604(1994). RN [31] RP VARIANTS VHLD. RX PubMed=7987306; DOI=10.1093/hmg/3.8.1303; RA Crossey P.A., Richards F.M., Foster K., Green J.S., Prowse A., Latif F., RA Lerman M.I., Zbar B., Affara N.A., Ferguson-Smith M.A., Maher E.R.; RT "Identification of intragenic mutations in the von Hippel-Lindau disease RT tumour suppressor gene and correlation with disease phenotype."; RL Hum. Mol. Genet. 3:1303-1308(1994). RN [32] RP VARIANTS VHLD. RX PubMed=7728151; DOI=10.1002/humu.1380050109; RA Chen F., Kishida T., Yao M., Hustad T., Glavac D., Dean M., Gnarra J.R., RA Orcutt M.L., Duh F.-M., Glenn G., Green J.S., Hsia Y.E., Lamiell J., Li H., RA Wei M.H., Schmidt L., Tory K., Kuzmin I., Stackhouse T., Latif F., RA Linehan W.M., Lerman M.I., Zbar B.; RT "Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: RT correlations with phenotype."; RL Hum. Mutat. 5:66-75(1995). RN [33] RP VARIANTS VHLD. RX PubMed=8634692; DOI=10.1093/hmg/4.12.2233; RA Kondo K., Sakai N., Kaneko S., Kobayashi K., Hosaka M., Ito S., Fujii S., RA Yamamoto I., Kim I., Miyagami M., Shidara N., Shinohara N., Koyanagi T., RA Kato N., Yamanaka H., Kuratu J., Fujioka M., Nakatsu H., Shimazaki J., RA Yoshida J., Sugita K., Hirao Y., Okajima E., Tanigawa T., Sato S., RA Fujino H., Nagata M., Kanayama H., Kagawa S., Yamashima T., Furuta T., RA Saito Y., Kanno H., Yao M., Shuin T.; RT "Germline mutations in the von Hippel-Lindau disease (VHL) gene in Japanese RT VHL. Clinical Research Group for VHL in Japan."; RL Hum. Mol. Genet. 4:2233-2237(1995). RN [34] RP VARIANTS VHLD LEU-84 AND TRP-167. RX PubMed=8592333; DOI=10.1136/jmg.32.11.885; RA Crossey P.A., Eng C., Ginalska-Malinowska M., Lennard T.W.J., Wheeler D.C., RA Ponder B.A.J., Maher E.R.; RT "Molecular genetic diagnosis of von Hippel-Lindau disease in familial RT phaeochromocytoma."; RL J. Med. Genet. 32:885-886(1995). RN [35] RP VARIANTS VHLD SER-114; SER-119; GLU-143 AND ARG-164. RX PubMed=8825918; DOI=10.1136/jmg.32.12.934; RA Eng C., Crossey P.A., Mulligan L.M., Healey C.S., Houghton C., Prowse A., RA Chew S.L., Dahia P.L.M., O'Riordan J.L.H., Toledo S.P.A., Smith D.P., RA Maher E.R., Ponder B.A.J.; RT "Mutations in the RET proto-oncogene and the von Hippel-Lindau disease RT tumour suppressor gene in sporadic and syndromic phaeochromocytomas."; RL J. Med. Genet. 32:934-937(1995). RN [36] RP VARIANTS VHLD PRO-96; VAL-116; ARG-118; PHE-166; ASP-170 AND GLU-186 DEL. RX PubMed=8730290; DOI=10.1136/jmg.33.4.328; RA Maher E.R., Webster A.R., Richards F.M., Green J.S., Crossey P.A., RA Payne S.J., Moore A.T.; RT "Phenotypic expression in von Hippel-Lindau disease: correlations with RT germline VHL gene mutations."; RL J. Med. Genet. 33:328-332(1996). RN [37] RP VARIANTS VHLD LEU-65; TRP-65; GLY-74; PHE-76 DEL; ILE-76; HIS-78; SER-78; RP THR-78; ARG-80; ASN-80; ILE-80; SER-81; ALA-86; LEU-86; ARG-88; SER-88; RP PRO-89; ARG-101; ARG-111; ASN-111; CYS-114; TYR-115; CYS-117; PRO-118; RP GLY-121; LEU-130; PRO-158; VAL-158; PRO-161; ARG-162; PHE-162; TYR-162; RP TRP-162; ARG-164; GLN-167; TRP-167; GLY-170; PRO-178; VAL-180; ARG-184; RP PRO-184; LYS-186; GLN-188 AND TRP-200. RX PubMed=8956040; RX DOI=10.1002/(sici)1098-1004(1996)8:4<348::aid-humu8>3.0.co;2-3; RA Zbar B., Kishida T., Chen F., Schmidt L., Maher E.R., Richards F.M., RA Crossey P.A., Webster A.R., Affara N.A., Ferguson-Smith M.A., Brauch H., RA Glavac D., Neumann H.P.H., Tisherman S., Mulvihill J.J., Gross D.J., RA Shuin T., Whaley J., Seizinger B., Kley N., Olschwang S., Boisson C., RA Richard S., Lips C.H.M., Linehan W.M., Lerman M.I.; RT "Germline mutations in the von Hippel-Lindau disease (VHL) gene in families RT from North America, Europe, and Japan."; RL Hum. Mutat. 8:348-357(1996). RN [38] RP VARIANTS VHLD PRO-38; LEU-76 AND PHE-162. RX PubMed=9452032; DOI=10.1002/humu.1380110111; RA Li C., Weber G., Ekman P., Lagercrantz J., Norlen B.J., Aakerstroem G., RA Nordenskjoeld M., Bergerheim U.S.R.; RT "Germline mutations detected in the von Hippel-Lindau disease tumor RT suppressor gene by Southern blot and direct genomic DNA sequencing."; RL Hum. Mutat. Suppl. 1:S31-S33(1998). RN [39] RP VARIANT VHLD THR-149. RX PubMed=9452106; DOI=10.1002/humu.1380110185; RA Mandich P., Montera M., Bellone E., Trojani A., Daniele S., Ajmar F.; RT "Three novel mutations in the von Hippel-Lindau tumour suppressor gene in RT Italian patients."; RL Hum. Mutat. Suppl. 1:S268-S270(1998). RN [40] RP VARIANT VHLD TRP-68. RX PubMed=10627136; RA Martin R., Hockey A., Walpole I., Goldblatt J.; RT "Variable penetrance of familial pheochromocytoma associated with the von RT Hippel-Lindau gene mutation, S68W."; RL Hum. Mutat. 12:71-71(1998). RN [41] RP VARIANTS VHLD TRP-65; SER-76; SER-81; ARG-86; ARG-88; GLY-101; PRO-107; RP ASN-111; CYS-117; THR-131; PHE-162; GLY-167; ASP-175; PRO-184 AND LYS-186. RX PubMed=9829911; RX DOI=10.1002/(sici)1098-1004(1998)12:6<417::aid-humu8>3.0.co;2-k; RA Stolle C., Glenn G., Zbar B., Humphrey J.S., Choyke P., Walther M., RA Pack S., Hurley K., Andrey C., Klausner R., Linehan W.M.; RT "Improved detection of germline mutations in the von Hippel-Lindau disease RT tumor suppressor gene."; RL Hum. Mutat. 12:417-423(1998). RN [42] RP VARIANTS VHLD LYS-52; LEU-65; LYS-70; ASN-80; ARG-80; SER-86; SER-88; RP LEU-91; ALA-104; PRO-105; GLN-115; CYS-117; PRO-118; LEU-130; LYS-131; RP SER-136; ASP-156; CYS-156; ILE-157; PRO-158; GLN-161; TRP-162; PHE-166; RP GLN-167; TRP-167; GLY-170; PRO-188 AND TRP-200. RX PubMed=9829912; RX DOI=10.1002/(sici)1098-1004(1998)12:6<424::aid-humu9>3.0.co;2-h; RA Olschwang S., Richard S., Boisson C., Giraud S., Laurent-Puig P., RA Resche F., Thomas G.; RT "Germline mutation profile of the VHL gene in von Hippel-Lindau disease and RT in sporadic hemangioblastoma."; RL Hum. Mutat. 12:424-430(1998). RN [43] RP VARIANTS PHEOCHROMOCYTOMA LEU-25; PRO-63; PRO-64 AND THR-147. RX PubMed=9663592; RX DOI=10.1002/(sici)1097-0215(19980729)77:3<337::aid-ijc5>3.0.co;2-p; RA van der Harst E., de Krijger R.R., Dinjens W.N.M., Weeks L.E., Bonjer H.J., RA Bruining H.A., Lamberts S.W.J., Koper J.W.; RT "Germline mutations in the vhl gene in patients presenting with RT phaeochromocytomas."; RL Int. J. Cancer 77:337-340(1998). RN [44] RP VARIANTS VHLD CYS-93; GLY-155 AND ILE-157. RA Murigia M.; RL Unpublished observations (MAY-1999). RN [45] RP VARIANT VHLD ASN-112. RX PubMed=10533030; RX DOI=10.1002/(sici)1096-8628(19991119)87:2<163::aid-ajmg7>3.0.co;2-a; RA Bradley J.F., Collins D.L., Schimke R.N., Parrott H.N., Rothberg P.G.; RT "Two distinct phenotypes caused by two different missense mutations in the RT same codon of the VHL gene."; RL Am. J. Med. Genet. 87:163-167(1999). RN [46] RP VARIANTS VHLD. RX PubMed=10408776; RX DOI=10.1002/(sici)1098-1004(1999)13:6<464::aid-humu6>3.0.co;2-a; RA Gallou C., Joly D., Mejean A., Staroz F., Martin N., Tarlet G., RA Orfanelli M.T., Bouvier R., Droz D., Chretien Y., Marechal J.M., RA Richard S., Junien C., Beroud C.; RT "Mutations of the VHL gene in sporadic renal cell carcinoma: definition of RT a risk factor for VHL patients to develop an RCC."; RL Hum. Mutat. 13:464-475(1999). RN [47] RP VARIANT RCC PRO-163, AND CHARACTERIZATION OF VARIANT RCC PRO-163. RX PubMed=11986208; DOI=10.1182/blood.v99.10.3562; RA Wiesener M.S., Seyfarth M., Warnecke C., Juergensen J.S., Rosenberger C., RA Morgan N.V., Maher E.R., Frei U., Eckardt K.-U.; RT "Paraneoplastic erythrocytosis associated with an inactivating point RT mutation of the von Hippel-Lindau gene in a renal cell carcinoma."; RL Blood 99:3562-3565(2002). RN [48] RP VARIANTS PHEOCHROMOCYTOMA ALA-65; TRP-68; ASN-80; SER-93; CYS-93; HIS-98; RP GLY-107; LEU-119; ILE-122; CYS-136; ASN-156; CYS-156; GLN-161; PRO-161; RP TRP-167; GLN-167; VAL-188 AND GLN-198. RX PubMed=12000816; DOI=10.1056/nejmoa020152; RG The Freiburg-Warsaw-Columbus pheochromocytoma study group; RA Neumann H.P.H., Bausch B., McWhinney S.R., Bender B.U., Gimm O., Franke G., RA Schipper J., Klisch J., Altehoefer C., Zerres K., Januszewicz A., RA Smith W.M., Munk R., Manz T., Glaesker S., Apel T.W., Treier M., RA Reineke M., Walz M.K., Hoang-Vu C., Brauckhoff M., Klein-Franke A., RA Klose P., Schmidt H., Maier-Woelfle M., Peczkowska M., Szmigielski C., RA Eng C.; RT "Germ-line mutations in nonsyndromic pheochromocytoma."; RL N. Engl. J. Med. 346:1459-1466(2002). RN [49] RP VARIANTS ECYT2 VAL-188; ASP-191; SER-192 AND TRP-200. RX PubMed=12844285; DOI=10.1086/377108; RA Pastore Y.D., Jedlickova K., Guan Y., Liu E., Fahner J., Hasle H., RA Prchal J.F., Prchal J.T.; RT "Mutations of von Hippel-Lindau tumor-suppressor gene and congenital RT polycythemia."; RL Am. J. Hum. Genet. 73:412-419(2003). RN [50] RP VARIANTS PHEOCHROMOCYTOMA LEU-25 AND CYS-156. RX PubMed=14500403; RA Gimenez-Roqueplo A.-P., Favier J., Rustin P., Rieubland C., Crespin M., RA Nau V., Khau Van Kien P., Corvol P., Plouin P.-F., Jeunemaitre X.; RT "Mutations in the SDHB gene are associated with extra-adrenal and/or RT malignant phaeochromocytomas."; RL Cancer Res. 63:5615-5621(2003). RN [51] RP ERRATUM OF PUBMED:14500403. RA Pastore Y.D., Jedlickova K., Guan Y., Liu E., Fahner J., Hasle H., RA Prchal J.F., Prchal J.T.; RL Am. J. Hum. Genet. 74:598-598(2004). RN [52] RP VARIANTS ECYT2 TYR-126; LEU-130 AND TRP-200. RX PubMed=12393546; DOI=10.1182/blood-2002-06-1843; RA Pastore Y.D., Jelinek J., Ang S., Guan Y., Liu E., Jedlickova K., RA Krishnamurti L., Prchal J.T.; RT "Mutations in the VHL gene in sporadic apparently congenital RT polycythemia."; RL Blood 101:1591-1595(2003). RN [53] RP VARIANT VHLD LEU-84. RX PubMed=16502427; DOI=10.1002/ajmg.a.31116; RA Abbott M.-A., Nathanson K.L., Nightingale S., Maher E.R., Greenstein R.M.; RT "The von Hippel-Lindau (VHL) germline mutation V84L manifests as early- RT onset bilateral pheochromocytoma."; RL Am. J. Med. Genet. A 140:685-690(2006). RN [54] RP VARIANTS [LARGE SCALE ANALYSIS] LEU-25 AND SER-86. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). CC -!- FUNCTION: Involved in the ubiquitination and subsequent proteasomal CC degradation via the von Hippel-Lindau ubiquitination complex CC (PubMed:10944113, PubMed:17981124, PubMed:19584355). Seems to act as a CC target recruitment subunit in the E3 ubiquitin ligase complex and CC recruits hydroxylated hypoxia-inducible factor (HIF) under normoxic CC conditions (PubMed:10944113, PubMed:17981124). Involved in CC transcriptional repression through interaction with HIF1A, HIF1AN and CC histone deacetylases (PubMed:10944113, PubMed:17981124). Ubiquitinates, CC in an oxygen-responsive manner, ADRB2 (PubMed:19584355). Acts as a CC negative regulator of mTORC1 by promoting ubiquitination and CC degradation of RPTOR (PubMed:34290272). {ECO:0000269|PubMed:10944113, CC ECO:0000269|PubMed:17981124, ECO:0000269|PubMed:19584355, CC ECO:0000269|PubMed:34290272}. CC -!- PATHWAY: Protein modification; protein ubiquitination. CC {ECO:0000269|PubMed:34290272}. CC -!- SUBUNIT: Component of the VCB (VHL-Elongin BC-CUL2) complex; this CC complex acts as a ubiquitin-ligase E3 and directs proteasome-dependent CC degradation of targeted proteins. Interacts with CUL2; this interaction CC is dependent on the integrity of the trimeric VCB complex. Interacts CC (via the beta domain) with HIF1A (via the NTAD domain); this CC interaction mediates degradation of HIF1A in normoxia and, in hypoxia, CC prevents ubiquitination and degradation of HIF1A by mediating hypoxia- CC induced translocation to the nucleus, a process which requires a CC hypoxia-dependent regulatory signal. Interacts with ADRB2; the CC interaction, in normoxia, is dependent on hydroxylation of ADRB2 and CC the subsequent VCB-mediated ubiquitination and degradation of ADRB2. CC Under hypoxia, hydroxylation, interaction with VHL, ubiquitination and CC subsequent degradation of ADRB2 are dramatically decreased. Interacts CC with RNF139, USP33 and JADE1. Found in a complex composed of LIMD1, CC VHL, EGLN1/PHD2, ELOB and CUL2. Isoform 1 and isoform 3 interact with CC LIMD1 (via LIM zinc-binding 2), AJUBA (via LIM domains) and WTIP (via CC LIM domains). Interacts with EPAS1. Interacts with CARD9. Interacts CC with DCUN1D1 independently of CUL2; this interaction engages DCUN1D1 in CC the VCB complex and triggers CUL2 neddylation and consequently cullin CC ring ligase (CRL) substrates polyubiquitylation (PubMed:23401859). CC Interacts with ALAS1 (hydroxylated form) (PubMed:16234850). CC {ECO:0000269|PubMed:10205047, ECO:0000269|PubMed:10635329, CC ECO:0000269|PubMed:10944113, ECO:0000269|PubMed:11384984, CC ECO:0000269|PubMed:11641274, ECO:0000269|PubMed:11739384, CC ECO:0000269|PubMed:12004076, ECO:0000269|PubMed:12032852, CC ECO:0000269|PubMed:12050673, ECO:0000269|PubMed:12169691, CC ECO:0000269|PubMed:16234850, ECO:0000269|PubMed:17981124, CC ECO:0000269|PubMed:19208626, ECO:0000269|PubMed:19584355, CC ECO:0000269|PubMed:22286099, ECO:0000269|PubMed:23401859, CC ECO:0000269|PubMed:7660130, ECO:0000269|PubMed:9122164}. CC -!- INTERACTION: CC P40337; Q13617: CUL2; NbExp=16; IntAct=EBI-301246, EBI-456179; CC P40337; P02751: FN1; NbExp=2; IntAct=EBI-301246, EBI-1220319; CC P40337; Q9UM11: FZR1; NbExp=2; IntAct=EBI-301246, EBI-724997; CC P40337; Q16665: HIF1A; NbExp=19; IntAct=EBI-301246, EBI-447269; CC P40337; P14866: HNRNPL; NbExp=2; IntAct=EBI-301246, EBI-719024; CC P40337; Q99750: MDFI; NbExp=4; IntAct=EBI-301246, EBI-724076; CC P40337; Q05513: PRKCZ; NbExp=3; IntAct=EBI-301246, EBI-295351; CC P40337; Q99873: PRMT1; NbExp=2; IntAct=EBI-301246, EBI-78738; CC P40337; P63244: RACK1; NbExp=9; IntAct=EBI-301246, EBI-296739; CC P40337; Q8WU17: RNF139; NbExp=2; IntAct=EBI-301246, EBI-1551681; CC P40337; P21980: TGM2; NbExp=10; IntAct=EBI-301246, EBI-727668; CC P40337; Q61221: Hif1a; Xeno; NbExp=2; IntAct=EBI-301246, EBI-298954; CC P40337; PRO_0000037322 [P0C6X7]: rep; Xeno; NbExp=7; IntAct=EBI-301246, EBI-25487235; CC P40337-1; Q9UM11: FZR1; NbExp=2; IntAct=EBI-3504450, EBI-724997; CC P40337-1; P08151: GLI1; NbExp=2; IntAct=EBI-3504450, EBI-308084; CC P40337-2; Q8WXK3: ASB13; NbExp=3; IntAct=EBI-12157263, EBI-707573; CC P40337-2; Q9Y575-3: ASB3; NbExp=3; IntAct=EBI-12157263, EBI-14199987; CC P40337-2; Q9H765: ASB8; NbExp=3; IntAct=EBI-12157263, EBI-3942509; CC P40337-2; Q99700-5: ATXN2; NbExp=3; IntAct=EBI-12157263, EBI-25891409; CC P40337-2; O14867: BACH1; NbExp=3; IntAct=EBI-12157263, EBI-1263541; CC P40337-2; A0A024R9H7: CCDC26; NbExp=3; IntAct=EBI-12157263, EBI-10271580; CC P40337-2; Q13939: CCIN; NbExp=3; IntAct=EBI-12157263, EBI-25879469; CC P40337-2; P24863: CCNC; NbExp=3; IntAct=EBI-12157263, EBI-395261; CC P40337-2; Q8TBB7: DCAF5; NbExp=3; IntAct=EBI-12157263, EBI-25895525; CC P40337-2; Q5TAQ9-2: DCAF8; NbExp=3; IntAct=EBI-12157263, EBI-25842815; CC P40337-2; Q92466: DDB2; NbExp=3; IntAct=EBI-12157263, EBI-1176171; CC P40337-2; Q9NX09: DDIT4; NbExp=3; IntAct=EBI-12157263, EBI-715104; CC P40337-2; G5E9A7: DMWD; NbExp=3; IntAct=EBI-12157263, EBI-10976677; CC P40337-2; Q01658: DR1; NbExp=3; IntAct=EBI-12157263, EBI-750300; CC P40337-2; Q9NZJ0: DTL; NbExp=3; IntAct=EBI-12157263, EBI-1176075; CC P40337-2; O75530-2: EED; NbExp=3; IntAct=EBI-12157263, EBI-11132357; CC P40337-2; Q9UI10: EIF2B4; NbExp=3; IntAct=EBI-12157263, EBI-2340132; CC P40337-2; Q8IYF1: ELOA2; NbExp=3; IntAct=EBI-12157263, EBI-741705; CC P40337-2; Q9H2C0: GAN; NbExp=3; IntAct=EBI-12157263, EBI-764342; CC P40337-2; P62879: GNB2; NbExp=3; IntAct=EBI-12157263, EBI-356942; CC P40337-2; Q9Y5Q9: GTF3C3; NbExp=3; IntAct=EBI-12157263, EBI-1054873; CC P40337-2; O75031: HSF2BP; NbExp=6; IntAct=EBI-12157263, EBI-7116203; CC P40337-2; P42858: HTT; NbExp=12; IntAct=EBI-12157263, EBI-466029; CC P40337-2; Q8WXH2: JPH3; NbExp=3; IntAct=EBI-12157263, EBI-1055254; CC P40337-2; Q9BVA0: KATNB1; NbExp=3; IntAct=EBI-12157263, EBI-11147603; CC P40337-2; O60333-2: KIF1B; NbExp=3; IntAct=EBI-12157263, EBI-10975473; CC P40337-2; Q9NR64: KLHL1; NbExp=3; IntAct=EBI-12157263, EBI-6426228; CC P40337-2; Q53G59: KLHL12; NbExp=3; IntAct=EBI-12157263, EBI-740929; CC P40337-2; Q6TDP4: KLHL17; NbExp=3; IntAct=EBI-12157263, EBI-21328926; CC P40337-2; Q8NBE8: KLHL23; NbExp=3; IntAct=EBI-12157263, EBI-2512246; CC P40337-2; O60662: KLHL41; NbExp=3; IntAct=EBI-12157263, EBI-5353084; CC P40337-2; Q8IXQ5-4: KLHL7; NbExp=3; IntAct=EBI-12157263, EBI-25895859; CC P40337-2; Q08380: LGALS3BP; NbExp=3; IntAct=EBI-12157263, EBI-354956; CC P40337-2; Q99750: MDFI; NbExp=4; IntAct=EBI-12157263, EBI-724076; CC P40337-2; Q96BF6: NACC2; NbExp=3; IntAct=EBI-12157263, EBI-3942475; CC P40337-2; P35240-4: NF2; NbExp=3; IntAct=EBI-12157263, EBI-1014514; CC P40337-2; O00746: NME4; NbExp=3; IntAct=EBI-12157263, EBI-744871; CC P40337-2; C9J082: NPHP1; NbExp=3; IntAct=EBI-12157263, EBI-25830675; CC P40337-2; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-12157263, EBI-1058491; CC P40337-2; Q9NV79: PCMTD2; NbExp=3; IntAct=EBI-12157263, EBI-6309018; CC P40337-2; Q8WWQ0: PHIP; NbExp=3; IntAct=EBI-12157263, EBI-722984; CC P40337-2; Q8TCD6: PHOSPHO2; NbExp=3; IntAct=EBI-12157263, EBI-2861380; CC P40337-2; O60260-5: PRKN; NbExp=3; IntAct=EBI-12157263, EBI-21251460; CC P40337-2; O14744: PRMT5; NbExp=3; IntAct=EBI-12157263, EBI-351098; CC P40337-2; Q8TAS3: PRRG2; NbExp=3; IntAct=EBI-12157263, EBI-10272071; CC P40337-2; Q9Y3C5: RNF11; NbExp=3; IntAct=EBI-12157263, EBI-396669; CC P40337-2; Q15393: SF3B3; NbExp=3; IntAct=EBI-12157263, EBI-346977; CC P40337-2; Q9GZS3: SKIC8; NbExp=3; IntAct=EBI-12157263, EBI-358545; CC P40337-2; Q8IYM2: SLFN12; NbExp=3; IntAct=EBI-12157263, EBI-2822550; CC P40337-2; P37840: SNCA; NbExp=3; IntAct=EBI-12157263, EBI-985879; CC P40337-2; O14508: SOCS2; NbExp=3; IntAct=EBI-12157263, EBI-617737; CC P40337-2; Q7Z699: SPRED1; NbExp=3; IntAct=EBI-12157263, EBI-5235340; CC P40337-2; Q96A44: SPSB4; NbExp=3; IntAct=EBI-12157263, EBI-2323233; CC P40337-2; Q13148: TARDBP; NbExp=3; IntAct=EBI-12157263, EBI-372899; CC P40337-2; O43493-5: TGOLN2; NbExp=3; IntAct=EBI-12157263, EBI-25830716; CC P40337-2; Q8NFB2: TMEM185A; NbExp=3; IntAct=EBI-12157263, EBI-21757569; CC P40337-2; P61086: UBE2K; NbExp=3; IntAct=EBI-12157263, EBI-473850; CC P40337-2; Q9C0C9: UBE2O; NbExp=3; IntAct=EBI-12157263, EBI-2339946; CC P40337-2; Q16763: UBE2S; NbExp=3; IntAct=EBI-12157263, EBI-2339823; CC P40337-2; Q5VVX9-2: UBE2U; NbExp=3; IntAct=EBI-12157263, EBI-21897992; CC P40337-2; Q8N0U8: VKORC1L1; NbExp=3; IntAct=EBI-12157263, EBI-11337915; CC P40337-2; Q9GZL7: WDR12; NbExp=3; IntAct=EBI-12157263, EBI-2490660; CC P40337-2; Q8N5D0-4: WDTC1; NbExp=3; IntAct=EBI-12157263, EBI-15821254; CC P40337-2; Q9Y6I7: WSB1; NbExp=3; IntAct=EBI-12157263, EBI-1171494; CC P40337-2; Q8NCP5-3: ZBTB44; NbExp=3; IntAct=EBI-12157263, EBI-25895743; CC P40337-2; Q6ZSB9: ZBTB49; NbExp=3; IntAct=EBI-12157263, EBI-2859943; CC P40337-2; Q15916: ZBTB6; NbExp=3; IntAct=EBI-12157263, EBI-7227791; CC P40337-2; P52739-2: ZNF131; NbExp=3; IntAct=EBI-12157263, EBI-10213055; CC P40337-2; Q96BH6; NbExp=3; IntAct=EBI-12157263, EBI-25872486; CC P40337-3; O75912: DGKI; NbExp=3; IntAct=EBI-301270, EBI-1765520; CC P40337-3; Q9UM11: FZR1; NbExp=2; IntAct=EBI-301270, EBI-724997; CC P40337-3; P08151: GLI1; NbExp=2; IntAct=EBI-301270, EBI-308084; CC P40337-3; Q15311: RALBP1; NbExp=3; IntAct=EBI-301270, EBI-749285; CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm CC {ECO:0000269|PubMed:9751722}. Cell membrane CC {ECO:0000269|PubMed:19584355}; Peripheral membrane protein CC {ECO:0000269|PubMed:9751722}. Endoplasmic reticulum CC {ECO:0000269|PubMed:12169691, ECO:0000269|PubMed:34290272}. Nucleus CC {ECO:0000269|PubMed:9751722}. Note=Found predominantly in the cytoplasm CC and with less amounts nuclear or membrane-associated (PubMed:9751722). CC Colocalizes with ADRB2 at the cell membrane (PubMed:19584355). CC {ECO:0000269|PubMed:19584355, ECO:0000269|PubMed:9751722}. CC -!- SUBCELLULAR LOCATION: [Isoform 3]: Cytoplasm CC {ECO:0000269|PubMed:9751722}. Nucleus {ECO:0000269|PubMed:9751722}. CC Note=Equally distributed between the nucleus and the cytoplasm but not CC membrane-associated. {ECO:0000269|PubMed:9751722}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing, Alternative initiation; Named isoforms=3; CC Name=1; Synonyms=VHL30, VHLp24(MPR); CC IsoId=P40337-1; Sequence=Displayed; CC Name=2; CC IsoId=P40337-2; Sequence=VSP_004488; CC Name=3; Synonyms=VHL19 {ECO:0000303|PubMed:9751722}, VHLp18(MEA); CC IsoId=P40337-3; Sequence=VSP_007740; CC -!- TISSUE SPECIFICITY: Expressed in the adult and fetal brain and kidney. CC -!- DEVELOPMENTAL STAGE: At 4-10 weeks pc, strong expression in the CC developing central nervous system, kidneys, testis and lung. CC Differentially expressed within renal tubules. CC {ECO:0000269|PubMed:8733131}. CC -!- DOMAIN: The Elongin BC complex binding domain is also known as BC-box CC with the consensus [APST]-L-x(3)-C-x(3)-[AILV]. CC -!- DISEASE: Pheochromocytoma (PCC) [MIM:171300]: A catecholamine-producing CC tumor of chromaffin tissue of the adrenal medulla or sympathetic CC paraganglia. The cardinal symptom, reflecting the increased secretion CC of epinephrine and norepinephrine, is hypertension, which may be CC persistent or intermittent. {ECO:0000269|PubMed:12000816, CC ECO:0000269|PubMed:14500403, ECO:0000269|PubMed:9663592}. Note=Disease CC susceptibility is associated with variants affecting the gene CC represented in this entry. CC -!- DISEASE: von Hippel-Lindau disease (VHLD) [MIM:193300]: VHLD is a CC dominantly inherited familial cancer syndrome predisposing to a variety CC of malignant and benign neoplasms, most frequently retinal, cerebellar CC and spinal hemangioblastoma, renal cell carcinoma (RCC), CC pheochromocytoma, and pancreatic tumors. VHL type 1 is without CC pheochromocytoma, type 2 is with pheochromocytoma. VHL type 2 is CC further subdivided into types 2A (pheochromocytoma, retinal angioma, CC and hemangioblastomas without renal cell carcinoma and pancreatic cyst) CC and 2B (pheochromocytoma, retinal angioma, and hemangioblastomas with CC renal cell carcinoma and pancreatic cyst). CC {ECO:0000269|PubMed:10408776, ECO:0000269|PubMed:10533030, CC ECO:0000269|PubMed:10627136, ECO:0000269|PubMed:10635329, CC ECO:0000269|PubMed:16502427, ECO:0000269|PubMed:7728151, CC ECO:0000269|PubMed:7987306, ECO:0000269|PubMed:8493574, CC ECO:0000269|PubMed:8592333, ECO:0000269|PubMed:8634692, CC ECO:0000269|PubMed:8730290, ECO:0000269|PubMed:8825918, CC ECO:0000269|PubMed:8956040, ECO:0000269|PubMed:9452032, CC ECO:0000269|PubMed:9452106, ECO:0000269|PubMed:9829911, CC ECO:0000269|PubMed:9829912, ECO:0000269|Ref.44}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Erythrocytosis, familial, 2 (ECYT2) [MIM:263400]: An autosomal CC recessive disorder characterized by an increase in serum red blood cell CC mass, hypersensitivity of erythroid progenitors to erythropoietin, CC increased erythropoietin serum levels, and normal oxygen affinity. CC Patients with ECYT2 carry a high risk for peripheral thrombosis and CC cerebrovascular events. {ECO:0000269|PubMed:12393546, CC ECO:0000269|PubMed:12844285}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Renal cell carcinoma (RCC) [MIM:144700]: Renal cell carcinoma CC is a heterogeneous group of sporadic or hereditary carcinoma derived CC from cells of the proximal renal tubular epithelium. It is CC subclassified into clear cell renal carcinoma (non-papillary CC carcinoma), papillary renal cell carcinoma, chromophobe renal cell CC carcinoma, collecting duct carcinoma with medullary carcinoma of the CC kidney, and unclassified renal cell carcinoma. Clear cell renal cell CC carcinoma is the most common subtype. {ECO:0000269|PubMed:11986208}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- MISCELLANEOUS: [Isoform 1]: Major isoform. CC -!- MISCELLANEOUS: [Isoform 3]: Produced by alternative initiation at Met- CC 54 of isoform 1. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the VHL family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/132/vhl-(von-hippel-lindau-tumor-suppressor)"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF010238; AAB64200.1; -; Genomic_DNA. DR EMBL; L15409; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; AK315799; BAG38142.1; -; mRNA. DR EMBL; AC034193; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471055; EAW64064.1; -; Genomic_DNA. DR EMBL; BC058831; AAH58831.1; -; mRNA. DR EMBL; U54612; AAA98614.1; -; Genomic_DNA. DR EMBL; X96489; CAA65343.1; -; Genomic_DNA. DR CCDS; CCDS2597.1; -. [P40337-1] DR CCDS; CCDS2598.1; -. [P40337-2] DR PIR; I38926; I38926. DR RefSeq; NP_000542.1; NM_000551.3. [P40337-1] DR RefSeq; NP_937799.1; NM_198156.2. [P40337-2] DR PDB; 1LM8; X-ray; 1.85 A; V=54-213. DR PDB; 1LQB; X-ray; 2.00 A; C=54-213. DR PDB; 1VCB; X-ray; 2.70 A; C/F/I/L=54-213. DR PDB; 3ZRC; X-ray; 2.90 A; C/F/I/L=54-213. DR PDB; 3ZRF; X-ray; 2.80 A; C/F/I/L=54-213. DR PDB; 3ZTC; X-ray; 2.65 A; C/F/I/L=54-213. DR PDB; 3ZTD; X-ray; 2.79 A; C/F/I/L=54-213. DR PDB; 3ZUN; X-ray; 2.50 A; C/F/I/L=54-213. DR PDB; 4AJY; X-ray; 1.73 A; V=54-213. DR PDB; 4AWJ; X-ray; 2.50 A; C/F/I/L=54-213. DR PDB; 4B95; X-ray; 2.80 A; C/F/I/L=54-213. DR PDB; 4B9K; X-ray; 2.00 A; C/F/I/L=54-213. DR PDB; 4BKS; X-ray; 2.20 A; C/F/I/L=54-213. DR PDB; 4BKT; X-ray; 2.35 A; C/F/I/L=54-213. DR PDB; 4W9C; X-ray; 2.20 A; C/F/I/L=54-213. DR PDB; 4W9D; X-ray; 2.20 A; C/F/I/L=54-213. DR PDB; 4W9E; X-ray; 2.60 A; C/F/I/L=54-213. DR PDB; 4W9F; X-ray; 2.10 A; C/F/I/L=54-213. DR PDB; 4W9G; X-ray; 2.70 A; C/F/I/L=54-213. DR PDB; 4W9H; X-ray; 2.10 A; C/F/I/L=54-213. DR PDB; 4W9I; X-ray; 2.40 A; C/F/I/L=54-213. DR PDB; 4W9J; X-ray; 2.20 A; C/F/I/L=54-213. DR PDB; 4W9K; X-ray; 2.10 A; C/F/I/L=54-213. DR PDB; 4W9L; X-ray; 2.20 A; C/F/I/L=54-213. DR PDB; 4WQO; X-ray; 3.20 A; A=1-213. DR PDB; 5LLI; X-ray; 2.40 A; C/F/I/L=54-213. DR PDB; 5N4W; X-ray; 3.90 A; V=54-213. DR PDB; 5NVV; X-ray; 2.10 A; C/F/I/L=54-213. DR PDB; 5NVW; X-ray; 2.20 A; C/F/I/L=54-213. DR PDB; 5NVX; X-ray; 2.20 A; C/F/I/L=54-213. DR PDB; 5NVY; X-ray; 2.90 A; C/F/I/L=54-213. DR PDB; 5NVZ; X-ray; 2.70 A; C/F/I/L=54-213. DR PDB; 5NW0; X-ray; 2.30 A; C/F/I/L=54-213. DR PDB; 5NW1; X-ray; 2.10 A; C/F/I/L=54-213. DR PDB; 5NW2; X-ray; 2.20 A; C/F/I/L=54-213. DR PDB; 5T35; X-ray; 2.70 A; D/H=54-213. DR PDB; 6BVB; X-ray; 2.00 A; V=54-213. DR PDB; 6FMI; X-ray; 2.80 A; C/F=54-204. DR PDB; 6FMJ; X-ray; 2.45 A; C/F/I/L=54-204. DR PDB; 6FMK; X-ray; 2.75 A; C/F/I/L=54-204. DR PDB; 6GFX; X-ray; 1.83 A; C=54-213. DR PDB; 6GFY; X-ray; 2.70 A; C/F/I/L=54-213. DR PDB; 6GFZ; X-ray; 2.30 A; C/F/I/L=54-213. DR PDB; 6GMN; X-ray; 1.94 A; C/F/I/L=54-213. DR PDB; 6GMQ; X-ray; 2.75 A; C/F/I/L=54-213. DR PDB; 6GMR; X-ray; 1.75 A; V=54-213. DR PDB; 6GMX; X-ray; 2.53 A; C/F/I/L=54-213. DR PDB; 6HAX; X-ray; 2.35 A; B/F=54-213. DR PDB; 6HAY; X-ray; 2.24 A; B/F=54-213. DR PDB; 6HR2; X-ray; 1.76 A; B/F=61-209. DR PDB; 6I7Q; X-ray; 1.80 A; V=54-213. DR PDB; 6I7R; X-ray; 1.95 A; V=54-213. DR PDB; 6R6H; EM; 8.40 A; V=60-207. DR PDB; 6R7F; EM; 8.20 A; V=54-213. DR PDB; 6SIS; X-ray; 3.50 A; D/H=54-213. DR PDB; 6ZHC; X-ray; 1.92 A; AAA=59-213. DR PDB; 7CJB; X-ray; 2.80 A; A/E/I/M=55-213. DR PDB; 7JTO; X-ray; 1.70 A; L=54-213. DR PDB; 7JTP; X-ray; 2.12 A; L=54-213. DR PDB; 7KHH; X-ray; 2.28 A; C=55-213. DR PDB; 7PI4; X-ray; 2.24 A; AAA=59-213. DR PDB; 7Q2J; X-ray; 2.50 A; C=54-213. DR PDB; 7S4E; X-ray; 2.25 A; B/F=54-213. DR PDB; 7Z6L; X-ray; 2.24 A; B=54-213. DR PDB; 7Z76; X-ray; 1.32 A; C=54-213. DR PDB; 7Z77; X-ray; 1.97 A; C=54-213. DR PDB; 7ZNT; X-ray; 3.00 A; C/F=54-213. DR PDB; 8BB2; X-ray; 2.05 A; L=54-213. DR PDB; 8BB3; X-ray; 1.80 A; L=54-213. DR PDB; 8BB4; X-ray; 2.80 A; P=54-213. DR PDB; 8BB5; X-ray; 2.20 A; C=54-213. DR PDB; 8BDI; X-ray; 2.11 A; C/F/I/L=54-213. DR PDB; 8BDJ; X-ray; 2.02 A; C/F/I/L=54-213. DR PDB; 8BDL; X-ray; 2.29 A; C/F/I/L=54-213. DR PDB; 8BDM; X-ray; 2.02 A; C/F/I/L=54-213. DR PDB; 8BDN; X-ray; 2.76 A; C/F/I/L=54-213. DR PDB; 8BDO; X-ray; 2.80 A; C/F=54-213. DR PDB; 8BDS; X-ray; 1.72 A; C=54-213. DR PDB; 8BDT; X-ray; 2.70 A; D/H=54-213. DR PDB; 8BDX; X-ray; 2.93 A; D/H=54-213. DR PDB; 8BEB; X-ray; 3.18 A; C=54-213. DR PDB; 8C13; X-ray; 2.30 A; L=54-213. DR PDB; 8CQE; X-ray; 2.85 A; C/F/I/L=54-213. DR PDB; 8CQK; X-ray; 2.62 A; C/F/I/L=54-213. DR PDB; 8CQL; X-ray; 2.38 A; C/F/I/L=54-213. DR PDB; 8EI3; X-ray; 3.49 A; C/F=54-213. DR PDB; 8EWV; X-ray; 3.40 A; C/G/K/O/S/W=54-213. DR PDB; 8G1P; X-ray; 2.70 A; C/F=56-213. DR PDB; 8G1Q; X-ray; 3.73 A; C=56-213. DR PDB; 8P0F; X-ray; 1.98 A; A/D=54-213. DR PDB; 8PC2; X-ray; 2.80 A; A/B=54-213. DR PDB; 8QU8; EM; 3.50 A; A=2-213. DR PDB; 8QVU; X-ray; 2.24 A; B/F=1-213. DR PDB; 8QW6; X-ray; 2.20 A; B/F=54-213. DR PDB; 8QW7; X-ray; 2.36 A; B/F=54-213. DR PDBsum; 1LM8; -. DR PDBsum; 1LQB; -. DR PDBsum; 1VCB; -. DR PDBsum; 3ZRC; -. DR PDBsum; 3ZRF; -. DR PDBsum; 3ZTC; -. DR PDBsum; 3ZTD; -. DR PDBsum; 3ZUN; -. DR PDBsum; 4AJY; -. DR PDBsum; 4AWJ; -. DR PDBsum; 4B95; -. DR PDBsum; 4B9K; -. DR PDBsum; 4BKS; -. DR PDBsum; 4BKT; -. DR PDBsum; 4W9C; -. DR PDBsum; 4W9D; -. DR PDBsum; 4W9E; -. DR PDBsum; 4W9F; -. DR PDBsum; 4W9G; -. DR PDBsum; 4W9H; -. DR PDBsum; 4W9I; -. DR PDBsum; 4W9J; -. DR PDBsum; 4W9K; -. DR PDBsum; 4W9L; -. DR PDBsum; 4WQO; -. DR PDBsum; 5LLI; -. DR PDBsum; 5N4W; -. DR PDBsum; 5NVV; -. DR PDBsum; 5NVW; -. DR PDBsum; 5NVX; -. DR PDBsum; 5NVY; -. DR PDBsum; 5NVZ; -. DR PDBsum; 5NW0; -. DR PDBsum; 5NW1; -. DR PDBsum; 5NW2; -. DR PDBsum; 5T35; -. DR PDBsum; 6BVB; -. DR PDBsum; 6FMI; -. DR PDBsum; 6FMJ; -. DR PDBsum; 6FMK; -. DR PDBsum; 6GFX; -. DR PDBsum; 6GFY; -. DR PDBsum; 6GFZ; -. DR PDBsum; 6GMN; -. DR PDBsum; 6GMQ; -. DR PDBsum; 6GMR; -. DR PDBsum; 6GMX; -. DR PDBsum; 6HAX; -. DR PDBsum; 6HAY; -. DR PDBsum; 6HR2; -. DR PDBsum; 6I7Q; -. DR PDBsum; 6I7R; -. DR PDBsum; 6R6H; -. DR PDBsum; 6R7F; -. DR PDBsum; 6SIS; -. DR PDBsum; 6ZHC; -. DR PDBsum; 7CJB; -. DR PDBsum; 7JTO; -. DR PDBsum; 7JTP; -. DR PDBsum; 7KHH; -. DR PDBsum; 7PI4; -. DR PDBsum; 7Q2J; -. DR PDBsum; 7S4E; -. DR PDBsum; 7Z6L; -. DR PDBsum; 7Z76; -. DR PDBsum; 7Z77; -. DR PDBsum; 7ZNT; -. DR PDBsum; 8BB2; -. DR PDBsum; 8BB3; -. DR PDBsum; 8BB4; -. DR PDBsum; 8BB5; -. DR PDBsum; 8BDI; -. DR PDBsum; 8BDJ; -. DR PDBsum; 8BDL; -. DR PDBsum; 8BDM; -. DR PDBsum; 8BDN; -. DR PDBsum; 8BDO; -. DR PDBsum; 8BDS; -. DR PDBsum; 8BDT; -. DR PDBsum; 8BDX; -. DR PDBsum; 8BEB; -. DR PDBsum; 8C13; -. DR PDBsum; 8CQE; -. DR PDBsum; 8CQK; -. DR PDBsum; 8CQL; -. DR PDBsum; 8EI3; -. DR PDBsum; 8EWV; -. DR PDBsum; 8G1P; -. DR PDBsum; 8G1Q; -. DR PDBsum; 8P0F; -. DR PDBsum; 8PC2; -. DR PDBsum; 8QU8; -. DR PDBsum; 8QVU; -. DR PDBsum; 8QW6; -. DR PDBsum; 8QW7; -. DR AlphaFoldDB; P40337; -. DR EMDB; EMD-4736; -. DR EMDB; EMD-4739; -. DR SASBDB; P40337; -. DR SMR; P40337; -. DR BioGRID; 113269; 577. DR ComplexPortal; CPX-2250; VHL-Elongin C-Elongin B E3 ubiquitin ligase complex. DR CORUM; P40337; -. DR DIP; DIP-32585N; -. DR IntAct; P40337; 136. DR MINT; P40337; -. DR STRING; 9606.ENSP00000256474; -. DR BindingDB; P40337; -. DR ChEMBL; CHEMBL3108660; -. DR GuidetoPHARMACOLOGY; 3204; -. DR iPTMnet; P40337; -. DR PhosphoSitePlus; P40337; -. DR BioMuta; VHL; -. DR DMDM; 4033778; -. DR EPD; P40337; -. DR jPOST; P40337; -. DR MassIVE; P40337; -. DR MaxQB; P40337; -. DR PaxDb; 9606-ENSP00000256474; -. DR PeptideAtlas; P40337; -. DR ProteomicsDB; 55362; -. [P40337-1] DR ProteomicsDB; 55363; -. [P40337-2] DR ProteomicsDB; 55364; -. [P40337-3] DR Pumba; P40337; -. DR Antibodypedia; 10562; 848 antibodies from 41 providers. DR DNASU; 7428; -. DR Ensembl; ENST00000256474.3; ENSP00000256474.3; ENSG00000134086.9. [P40337-1] DR Ensembl; ENST00000345392.2; ENSP00000344757.2; ENSG00000134086.9. [P40337-2] DR GeneID; 7428; -. DR KEGG; hsa:7428; -. DR MANE-Select; ENST00000256474.3; ENSP00000256474.3; NM_000551.4; NP_000542.1. DR UCSC; uc003bvc.4; human. [P40337-1] DR AGR; HGNC:12687; -. DR CTD; 7428; -. DR DisGeNET; 7428; -. DR GeneCards; VHL; -. DR GeneReviews; VHL; -. DR HGNC; HGNC:12687; VHL. DR HPA; ENSG00000134086; Low tissue specificity. DR MalaCards; VHL; -. DR MIM; 144700; phenotype. DR MIM; 171300; phenotype. DR MIM; 193300; phenotype. DR MIM; 263400; phenotype. DR MIM; 608537; gene. DR neXtProt; NX_P40337; -. DR OpenTargets; ENSG00000134086; -. DR Orphanet; 238557; Chuvash erythrocytosis. DR Orphanet; 29072; Hereditary pheochromocytoma-paraganglioma. DR Orphanet; 276621; Sporadic pheochromocytoma/secreting paraganglioma. DR Orphanet; 892; Von Hippel-Lindau disease. DR PharmGKB; PA37307; -. DR VEuPathDB; HostDB:ENSG00000134086; -. DR eggNOG; KOG4710; Eukaryota. DR GeneTree; ENSGT00390000014353; -. DR HOGENOM; CLU_116090_0_0_1; -. DR InParanoid; P40337; -. DR OMA; VGHPWLF; -. DR OrthoDB; 2951928at2759; -. DR PhylomeDB; P40337; -. DR TreeFam; TF318985; -. DR BRENDA; 2.3.2.B13; 2681. DR PathwayCommons; P40337; -. DR Reactome; R-HSA-1234176; Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha. DR Reactome; R-HSA-3232142; SUMOylation of ubiquitinylation proteins. DR Reactome; R-HSA-8951664; Neddylation. DR Reactome; R-HSA-9682706; Replication of the SARS-CoV-1 genome. DR Reactome; R-HSA-9694686; Replication of the SARS-CoV-2 genome. DR Reactome; R-HSA-9706019; RHOBTB3 ATPase cycle. DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation. DR SignaLink; P40337; -. DR SIGNOR; P40337; -. DR UniPathway; UPA00143; -. DR BioGRID-ORCS; 7428; 646 hits in 1234 CRISPR screens. DR ChiTaRS; VHL; human. DR EvolutionaryTrace; P40337; -. DR GeneWiki; Von_Hippel%E2%80%93Lindau_tumor_suppressor; -. DR GenomeRNAi; 7428; -. DR Pharos; P40337; Tchem. DR PRO; PR:P40337; -. DR Proteomes; UP000005640; Chromosome 3. DR RNAct; P40337; Protein. DR Bgee; ENSG00000134086; Expressed in cortical plate and 112 other cell types or tissues. DR ExpressionAtlas; P40337; baseline and differential. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0043232; C:intracellular non-membrane-bounded organelle; EXP:DisProt. DR GO; GO:0005739; C:mitochondrion; NAS:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; TAS:ProtInc. DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell. DR GO; GO:0140297; F:DNA-binding transcription factor binding; IPI:UniProtKB. DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB. DR GO; GO:0060090; F:molecular adaptor activity; EXP:DisProt. DR GO; GO:0003714; F:transcription corepressor activity; IEP:DisProt. DR GO; GO:0003711; F:transcription elongation factor activity; IDA:UniProtKB. DR GO; GO:1990756; F:ubiquitin ligase-substrate adaptor activity; IDA:UniProtKB. DR GO; GO:0004842; F:ubiquitin-protein transferase activity; TAS:Reactome. DR GO; GO:1990000; P:amyloid fibril formation; IDA:DisProt. DR GO; GO:0000902; P:cell morphogenesis; NAS:UniProtKB. DR GO; GO:0071456; P:cellular response to hypoxia; TAS:Reactome. DR GO; GO:0043066; P:negative regulation of apoptotic process; NAS:UniProtKB. DR GO; GO:0010507; P:negative regulation of autophagy; IDA:DisProt. DR GO; GO:0008285; P:negative regulation of cell population proliferation; IDA:DisProt. DR GO; GO:0010629; P:negative regulation of gene expression; IMP:CAFA. DR GO; GO:0046426; P:negative regulation of receptor signaling pathway via JAK-STAT; IMP:CAFA. DR GO; GO:0009968; P:negative regulation of signal transduction; EXP:DisProt. DR GO; GO:1904262; P:negative regulation of TORC1 signaling; IDA:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0034244; P:negative regulation of transcription elongation by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0045597; P:positive regulation of cell differentiation; NAS:UniProtKB. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IMP:UniProtKB. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IDA:UniProtKB. DR GO; GO:0050821; P:protein stabilization; NAS:UniProtKB. DR GO; GO:0016567; P:protein ubiquitination; IDA:ParkinsonsUK-UCL. DR GO; GO:0006508; P:proteolysis; TAS:ProtInc. DR GO; GO:1900037; P:regulation of cellular response to hypoxia; EXP:DisProt. DR GO; GO:0006355; P:regulation of DNA-templated transcription; IMP:BHF-UCL. DR GO; GO:0010468; P:regulation of gene expression; IDA:DisProt. DR CDD; cd05468; pVHL; 1. DR DisProt; DP00287; -. DR Gene3D; 1.10.750.10; von Hippel-Lindau disease tumour suppressor, alpha domain; 1. DR Gene3D; 2.60.40.780; von Hippel-Lindau disease tumour suppressor, beta domain; 1. DR IDEAL; IID00371; -. DR InterPro; IPR024048; VHL_alpha_dom. DR InterPro; IPR037139; VHL_alpha_dom_sf. DR InterPro; IPR024053; VHL_beta_dom. DR InterPro; IPR037140; VHL_beta_dom_sf. DR InterPro; IPR036208; VHL_sf. DR InterPro; IPR022772; VHL_tumour_suppress_b/a_dom. DR PANTHER; PTHR15160:SF1; VON HIPPEL-LINDAU DISEASE TUMOR SUPPRESSOR; 1. DR PANTHER; PTHR15160; VON HIPPEL-LINDAU PROTEIN; 1. DR Pfam; PF01847; VHL; 1. DR Pfam; PF17211; VHL_C; 1. DR SUPFAM; SSF49468; VHL; 1. DR Genevisible; P40337; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative initiation; Alternative splicing; Cell membrane; KW Congenital erythrocytosis; Cytoplasm; Disease variant; KW Endoplasmic reticulum; Membrane; Nucleus; Reference proteome; Repeat; KW Tumor suppressor; Ubl conjugation pathway. FT CHAIN 1..213 FT /note="von Hippel-Lindau disease tumor suppressor" FT /id="PRO_0000065809" FT REPEAT 14..18 FT /note="1" FT REPEAT 19..23 FT /note="2" FT REPEAT 24..28 FT /note="3" FT REPEAT 29..33 FT /note="4" FT REPEAT 34..38 FT /note="5" FT REPEAT 39..43 FT /note="6" FT REPEAT 44..48 FT /note="7" FT REPEAT 49..53 FT /note="8" FT REGION 1..65 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 14..53 FT /note="8 X 5 AA tandem repeats of G-[PAVG]-E-E-[DAYSLE]" FT REGION 100..155 FT /note="Involved in binding to CCT complex" FT REGION 157..166 FT /note="Interaction with Elongin BC complex" FT COMPBIAS 12..50 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT VAR_SEQ 1..53 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000305" FT /id="VSP_007740" FT VAR_SEQ 114..154 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_004488" FT VARIANT 25 FT /note="P -> L (in pheochromocytoma; likely benign; FT dbSNP:rs35460768)" FT /evidence="ECO:0000269|PubMed:14500403, FT ECO:0000269|PubMed:17344846, ECO:0000269|PubMed:9663592" FT /id="VAR_034562" FT VARIANT 38 FT /note="S -> P (in VHLD; type II)" FT /evidence="ECO:0000269|PubMed:9452032" FT /id="VAR_005670" FT VARIANT 52 FT /note="E -> K (in VHLD; type I; dbSNP:rs373068386)" FT /evidence="ECO:0000269|PubMed:9829912" FT /id="VAR_005671" FT VARIANT 63 FT /note="L -> P (in pheochromocytoma; dbSNP:rs104893827)" FT /evidence="ECO:0000269|PubMed:9663592" FT /id="VAR_034987" FT VARIANT 64 FT /note="R -> P (in pheochromocytoma; dbSNP:rs104893826)" FT /evidence="ECO:0000269|PubMed:9663592" FT /id="VAR_034988" FT VARIANT 65 FT /note="S -> A (in pheochromocytoma; dbSNP:rs869025616)" FT /evidence="ECO:0000269|PubMed:12000816" FT /id="VAR_034989" FT VARIANT 65 FT /note="S -> L (in VHLD; type I; dbSNP:rs5030826)" FT /evidence="ECO:0000269|PubMed:8956040, FT ECO:0000269|PubMed:9829912" FT /id="VAR_005672" FT VARIANT 65 FT /note="S -> W (in VHLD; type I; dbSNP:rs5030826)" FT /evidence="ECO:0000269|PubMed:8956040, FT ECO:0000269|PubMed:9829911" FT /id="VAR_005673" FT VARIANT 66..73 FT /note="Missing (in VHLD; type I)" FT /id="VAR_005674" FT VARIANT 68 FT /note="S -> W (in pheochromocytoma and VHLD; type II)" FT /evidence="ECO:0000269|PubMed:10627136, FT ECO:0000269|PubMed:12000816" FT /id="VAR_005675" FT VARIANT 70 FT /note="E -> K (in VHLD; type I; dbSNP:rs5030802)" FT /evidence="ECO:0000269|PubMed:9829912" FT /id="VAR_005676" FT VARIANT 74 FT /note="V -> G (in VHLD; type I-II; dbSNP:rs5030803)" FT /evidence="ECO:0000269|PubMed:8956040" FT /id="VAR_005677" FT VARIANT 75 FT /note="Missing (in VHLD; dbSNP:rs794729660)" FT /evidence="ECO:0000269|PubMed:8493574" FT /id="VAR_034990" FT VARIANT 76 FT /note="F -> I (in VHLD; type I; dbSNP:rs1559425911)" FT /evidence="ECO:0000269|PubMed:8956040" FT /id="VAR_005679" FT VARIANT 76 FT /note="F -> L (in VHLD; type I)" FT /evidence="ECO:0000269|PubMed:9452032" FT /id="VAR_005680" FT VARIANT 76 FT /note="F -> S (in VHLD; type I; dbSNP:rs730882033)" FT /evidence="ECO:0000269|PubMed:9829911" FT /id="VAR_005681" FT VARIANT 76 FT /note="Missing (in VHLD; type I; common mutation)" FT /evidence="ECO:0000269|PubMed:8956040" FT /id="VAR_005678" FT VARIANT 78 FT /note="N -> H (in VHLD; type I; dbSNP:rs869025621)" FT /evidence="ECO:0000269|PubMed:8956040" FT /id="VAR_005682" FT VARIANT 78 FT /note="N -> S (in VHLD; type I; common mutation; FT dbSNP:rs5030804)" FT /evidence="ECO:0000269|PubMed:8956040" FT /id="VAR_005683" FT VARIANT 78 FT /note="N -> T (in VHLD; type I; dbSNP:rs5030804)" FT /evidence="ECO:0000269|PubMed:8956040" FT /id="VAR_005684" FT VARIANT 79 FT /note="R -> P (in VHLD)" FT /id="VAR_005685" FT VARIANT 80 FT /note="S -> I (in VHLD; type I; dbSNP:rs5030805)" FT /evidence="ECO:0000269|PubMed:8956040" FT /id="VAR_005686" FT VARIANT 80 FT /note="S -> N (in pheochromocytoma and VHLD; type I; FT dbSNP:rs5030805)" FT /evidence="ECO:0000269|PubMed:12000816, FT ECO:0000269|PubMed:8956040, ECO:0000269|PubMed:9829912" FT /id="VAR_005688" FT VARIANT 80 FT /note="S -> R (in VHLD; type I; dbSNP:rs786202787)" FT /evidence="ECO:0000269|PubMed:8956040, FT ECO:0000269|PubMed:9829912" FT /id="VAR_005687" FT VARIANT 81 FT /note="P -> S (in VHLD; type I; dbSNP:rs104893829)" FT /evidence="ECO:0000269|PubMed:8956040, FT ECO:0000269|PubMed:9829911" FT /id="VAR_005689" FT VARIANT 82..84 FT /note="Missing (in VHLD)" FT /evidence="ECO:0000269|PubMed:8493574" FT /id="VAR_005691" FT VARIANT 82 FT /note="R -> P (in VHLD; type I; dbSNP:rs794726890)" FT /id="VAR_005690" FT VARIANT 84 FT /note="V -> L (in VHLD; type II and type 2C; FT dbSNP:rs5030827)" FT /evidence="ECO:0000269|PubMed:16502427, FT ECO:0000269|PubMed:8592333" FT /id="VAR_005692" FT VARIANT 86 FT /note="P -> A (in VHLD; type I; dbSNP:rs398123481)" FT /evidence="ECO:0000269|PubMed:8956040" FT /id="VAR_005693" FT VARIANT 86 FT /note="P -> H (in VHLD)" FT /id="VAR_008097" FT VARIANT 86 FT /note="P -> L (in VHLD; type I; dbSNP:rs730882034)" FT /evidence="ECO:0000269|PubMed:8956040" FT /id="VAR_005694" FT VARIANT 86 FT /note="P -> R (in VHLD; type I; dbSNP:rs730882034)" FT /evidence="ECO:0000269|PubMed:9829911" FT /id="VAR_005695" FT VARIANT 86 FT /note="P -> S (in VHLD; dbSNP:rs398123481)" FT /evidence="ECO:0000269|PubMed:17344846, FT ECO:0000269|PubMed:9829912" FT /id="VAR_005696" FT VARIANT 88 FT /note="W -> R (in VHLD; type I; dbSNP:rs1553619431)" FT /evidence="ECO:0000269|PubMed:8956040, FT ECO:0000269|PubMed:9829911" FT /id="VAR_005697" FT VARIANT 88 FT /note="W -> S (in VHLD; type I; dbSNP:rs119103277)" FT /evidence="ECO:0000269|PubMed:8956040, FT ECO:0000269|PubMed:9829912" FT /id="VAR_005698" FT VARIANT 89 FT /note="L -> H (in lung cancer; dbSNP:rs5030807)" FT /id="VAR_005699" FT VARIANT 89 FT /note="L -> P (in VHLD; type I; dbSNP:rs5030807)" FT /evidence="ECO:0000269|PubMed:8956040" FT /id="VAR_005700" FT VARIANT 91 FT /note="F -> L (in cerebellar hemangioblastoma; FT dbSNP:rs1060503563)" FT /evidence="ECO:0000269|PubMed:9829912" FT /id="VAR_005701" FT VARIANT 92..97 FT /note="Missing (in VHLD; type I)" FT /id="VAR_005702" FT VARIANT 93 FT /note="G -> C (in pheochromocytoma and VHLD; type II; FT dbSNP:rs5030808)" FT /evidence="ECO:0000269|PubMed:12000816, ECO:0000269|Ref.44" FT /id="VAR_005703" FT VARIANT 93 FT /note="G -> D (in VHLD; dbSNP:rs1553619440)" FT /id="VAR_005704" FT VARIANT 93 FT /note="G -> S (in pheochromocytoma and VHLD; type II; FT dbSNP:rs5030808)" FT /evidence="ECO:0000269|PubMed:12000816" FT /id="VAR_005705" FT VARIANT 96 FT /note="Q -> P (in VHLD; type I; dbSNP:rs1559426089)" FT /evidence="ECO:0000269|PubMed:8730290" FT /id="VAR_005706" FT VARIANT 98 FT /note="Y -> H (in pheochromocytoma and VHLD; type II; FT dbSNP:rs5030809)" FT /evidence="ECO:0000269|PubMed:12000816" FT /id="VAR_005707" FT VARIANT 101 FT /note="L -> G (in VHLD; type I; requires 2 nucleotide FT substitutions)" FT /evidence="ECO:0000269|PubMed:9829911" FT /id="VAR_005708" FT VARIANT 101 FT /note="L -> R (in VHLD; type I)" FT /evidence="ECO:0000269|PubMed:8956040" FT /id="VAR_005709" FT VARIANT 104 FT /note="G -> A (in cerebellar hemangioblastoma; FT dbSNP:rs869025630)" FT /evidence="ECO:0000269|PubMed:9829912" FT /id="VAR_005710" FT VARIANT 105 FT /note="T -> P (in VHLD; type I; dbSNP:rs1553619461)" FT /evidence="ECO:0000269|PubMed:9829912" FT /id="VAR_005711" FT VARIANT 106 FT /note="G -> D (in lung cancer; dbSNP:rs1446876735)" FT /id="VAR_005712" FT VARIANT 107 FT /note="R -> G (in pheochromocytoma; dbSNP:rs397516440)" FT /evidence="ECO:0000269|PubMed:12000816" FT /id="VAR_034991" FT VARIANT 107 FT /note="R -> P (in VHLD; type I; dbSNP:rs193922609)" FT /evidence="ECO:0000269|PubMed:9829911" FT /id="VAR_005713" FT VARIANT 110 FT /note="H -> Y (in dbSNP:rs17855706)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_055087" FT VARIANT 111 FT /note="S -> C (in VHLD; type II; dbSNP:rs1559426203)" FT /id="VAR_005714" FT VARIANT 111 FT /note="S -> N (in VHLD; type I; dbSNP:rs869025631)" FT /evidence="ECO:0000269|PubMed:8956040, FT ECO:0000269|PubMed:9829911" FT /id="VAR_005715" FT VARIANT 111 FT /note="S -> R (in VHLD; type I; dbSNP:rs765978945)" FT /evidence="ECO:0000269|PubMed:8956040" FT /id="VAR_005716" FT VARIANT 112 FT /note="Y -> H (in VHLD; type IIA; dbSNP:rs104893824)" FT /id="VAR_005717" FT VARIANT 112 FT /note="Y -> N (in VHLD; dbSNP:rs104893824)" FT /evidence="ECO:0000269|PubMed:10533030" FT /id="VAR_034992" FT VARIANT 114 FT /note="G -> C (in VHLD; type II)" FT /evidence="ECO:0000269|PubMed:8956040" FT /id="VAR_005718" FT VARIANT 114 FT /note="G -> R (in VHLD; type I-II; dbSNP:rs869025636)" FT /id="VAR_005719" FT VARIANT 114 FT /note="G -> S (in VHLD; type II; dbSNP:rs869025636)" FT /evidence="ECO:0000269|PubMed:8825918" FT /id="VAR_005720" FT VARIANT 115 FT /note="H -> Q (in VHLD; type II; dbSNP:rs864622646)" FT /evidence="ECO:0000269|PubMed:9829912" FT /id="VAR_005723" FT VARIANT 115 FT /note="H -> R (in VHLD; type II; dbSNP:rs5030812)" FT /id="VAR_008098" FT VARIANT 115 FT /note="H -> Y (in VHLD; type I; dbSNP:rs5030811)" FT /evidence="ECO:0000269|PubMed:8956040" FT /id="VAR_005722" FT VARIANT 116 FT /note="L -> V (in VHLD)" FT /evidence="ECO:0000269|PubMed:8730290" FT /id="VAR_005724" FT VARIANT 117 FT /note="W -> C (in VHLD; type I; dbSNP:rs727504215)" FT /evidence="ECO:0000269|PubMed:8956040, FT ECO:0000269|PubMed:9829911, ECO:0000269|PubMed:9829912" FT /id="VAR_005725" FT VARIANT 118 FT /note="L -> P (in VHLD; type I; dbSNP:rs5030830)" FT /evidence="ECO:0000269|PubMed:8956040, FT ECO:0000269|PubMed:9829912" FT /id="VAR_005726" FT VARIANT 118 FT /note="L -> R (in VHLD; dbSNP:rs5030830)" FT /evidence="ECO:0000269|PubMed:8730290" FT /id="VAR_005727" FT VARIANT 119 FT /note="F -> L (in pheochromocytoma and VHLD; type II; FT dbSNP:rs1553619948)" FT /evidence="ECO:0000269|PubMed:12000816" FT /id="VAR_005728" FT VARIANT 119 FT /note="F -> S (in VHLD; type II)" FT /evidence="ECO:0000269|PubMed:8825918" FT /id="VAR_005729" FT VARIANT 121 FT /note="D -> G (in VHLD; type I; dbSNP:rs5030832)" FT /evidence="ECO:0000269|PubMed:8956040" FT /id="VAR_005730" FT VARIANT 122 FT /note="A -> I (in pheochromocytoma; requires 2 nucleotide FT substitutions)" FT /evidence="ECO:0000269|PubMed:12000816" FT /id="VAR_034993" FT VARIANT 126 FT /note="D -> Y (in ECYT2; dbSNP:rs104893831)" FT /evidence="ECO:0000269|PubMed:12393546" FT /id="VAR_034994" FT VARIANT 128 FT /note="L -> F (in VHLD; type II; dbSNP:rs1553619956)" FT /id="VAR_005731" FT VARIANT 129 FT /note="L -> LE (in VHLD)" FT /id="VAR_005732" FT VARIANT 130 FT /note="V -> L (in ECYT2 and VHLD; type I; FT dbSNP:rs104893830)" FT /evidence="ECO:0000269|PubMed:12393546, FT ECO:0000269|PubMed:8956040, ECO:0000269|PubMed:9829912" FT /id="VAR_005733" FT VARIANT 131 FT /note="N -> K (in VHLD; type I; dbSNP:rs1064794272)" FT /evidence="ECO:0000269|PubMed:9829912" FT /id="VAR_005734" FT VARIANT 131 FT /note="N -> T (in VHLD; type I)" FT /evidence="ECO:0000269|PubMed:9829911" FT /id="VAR_005735" FT VARIANT 135 FT /note="L -> F (in hemangioblastoma; dbSNP:rs119103278)" FT /evidence="ECO:0000269|PubMed:8069849" FT /id="VAR_034995" FT VARIANT 136 FT /note="F -> C (in pheochromocytoma and VHLD; type II; FT dbSNP:rs5030833)" FT /evidence="ECO:0000269|PubMed:12000816" FT /id="VAR_005737" FT VARIANT 136 FT /note="F -> S (in VHLD; dbSNP:rs5030833)" FT /evidence="ECO:0000269|PubMed:9829912" FT /id="VAR_005736" FT VARIANT 136 FT /note="F -> Y (in VHLD)" FT /id="VAR_008099" FT VARIANT 143 FT /note="D -> E (in VHLD; type II; dbSNP:rs773556807)" FT /evidence="ECO:0000269|PubMed:8825918" FT /id="VAR_005738" FT VARIANT 145 FT /note="Q -> H (in VHLD; dbSNP:rs771727849)" FT /id="VAR_008100" FT VARIANT 147 FT /note="I -> T (in pheochromocytoma; dbSNP:rs1060503555)" FT /evidence="ECO:0000269|PubMed:9663592" FT /id="VAR_034996" FT VARIANT 148 FT /note="Missing (in VHLD; type I)" FT /id="VAR_005739" FT VARIANT 149 FT /note="A -> T (in VHLD; type II; dbSNP:rs587780077)" FT /evidence="ECO:0000269|PubMed:9452106" FT /id="VAR_005740" FT VARIANT 154 FT /note="P -> L (in VHLD; type II; dbSNP:rs1399097617)" FT /id="VAR_005741" FT VARIANT 155 FT /note="V -> G (in VHLD; type II)" FT /evidence="ECO:0000269|Ref.44" FT /id="VAR_005742" FT VARIANT 155 FT /note="V -> M (in VHLD; with RCC; dbSNP:rs869025659)" FT /id="VAR_008101" FT VARIANT 156 FT /note="Y -> C (in pheochromocytoma and VHLD; type I; FT dbSNP:rs397516441)" FT /evidence="ECO:0000269|PubMed:12000816, FT ECO:0000269|PubMed:14500403, ECO:0000269|PubMed:9829912" FT /id="VAR_005743" FT VARIANT 156 FT /note="Y -> D (in VHLD; type I)" FT /evidence="ECO:0000269|PubMed:9829912" FT /id="VAR_005744" FT VARIANT 156 FT /note="Y -> N (in pheochromocytoma)" FT /evidence="ECO:0000269|PubMed:12000816" FT /id="VAR_034997" FT VARIANT 157 FT /note="T -> I (in VHLD; type II; dbSNP:rs869025660)" FT /evidence="ECO:0000269|PubMed:9829912, ECO:0000269|Ref.44" FT /id="VAR_005746" FT VARIANT 157 FT /note="T -> TF (in VHLD; type I)" FT /id="VAR_005747" FT VARIANT 158 FT /note="L -> P (in VHLD; type I-II; abolishes release from FT chaperonin complex and the interaction with Elongin BC FT complex; dbSNP:rs121913346)" FT /evidence="ECO:0000269|PubMed:10635329, FT ECO:0000269|PubMed:8956040, ECO:0000269|PubMed:9829912" FT /id="VAR_005748" FT VARIANT 158 FT /note="L -> V (in VHLD; type I; dbSNP:rs1559429613)" FT /evidence="ECO:0000269|PubMed:8956040" FT /id="VAR_005749" FT VARIANT 159 FT /note="K -> E (in VHLD; type II; dbSNP:rs1575932011)" FT /id="VAR_005750" FT VARIANT 161 FT /note="R -> G (in VHLD; type II; dbSNP:rs5030818)" FT /id="VAR_005753" FT VARIANT 161 FT /note="R -> P (in pheochromocytoma and VHLD; type I)" FT /evidence="ECO:0000269|PubMed:12000816, FT ECO:0000269|PubMed:8956040" FT /id="VAR_005752" FT VARIANT 161 FT /note="R -> Q (in pheochromocytoma and VHLD; type II; FT dbSNP:rs730882035)" FT /evidence="ECO:0000269|PubMed:12000816, FT ECO:0000269|PubMed:9829912" FT /id="VAR_005751" FT VARIANT 162 FT /note="C -> F (in VHLD; type I; No effect on interaction FT with HIF1A nor on HIF1A degradation; dbSNP:rs397516444)" FT /evidence="ECO:0000269|PubMed:10944113, FT ECO:0000269|PubMed:8956040, ECO:0000269|PubMed:9452032, FT ECO:0000269|PubMed:9829911" FT /id="VAR_005754" FT VARIANT 162 FT /note="C -> R (in VHLD; type I; dbSNP:rs1553620313)" FT /evidence="ECO:0000269|PubMed:8956040" FT /id="VAR_005755" FT VARIANT 162 FT /note="C -> W (in VHLD; type I-II; dbSNP:rs5030622)" FT /evidence="ECO:0000269|PubMed:8956040, FT ECO:0000269|PubMed:9829912" FT /id="VAR_005756" FT VARIANT 162 FT /note="C -> Y (in VHLD; type I; dbSNP:rs397516444)" FT /evidence="ECO:0000269|PubMed:8956040" FT /id="VAR_005757" FT VARIANT 163 FT /note="L -> P (in RCC; with paraneoplastic erythrocytosis; FT inhibits binding to HIF1AN; dbSNP:rs28940297)" FT /evidence="ECO:0000269|PubMed:11986208, ECO:0000269|Ref.6" FT /id="VAR_034998" FT VARIANT 164 FT /note="Q -> H (in VHLD; dbSNP:rs1352275281)" FT /id="VAR_008102" FT VARIANT 164 FT /note="Q -> R (in VHLD; type II; dbSNP:rs267607170)" FT /evidence="ECO:0000269|PubMed:8825918, FT ECO:0000269|PubMed:8956040" FT /id="VAR_005758" FT VARIANT 166 FT /note="V -> D (in VHLD; with RCC; dbSNP:rs397516445)" FT /id="VAR_008103" FT VARIANT 166 FT /note="V -> F (in VHLD; type IIA; dbSNP:rs104893825)" FT /evidence="ECO:0000269|PubMed:8730290, FT ECO:0000269|PubMed:9829912" FT /id="VAR_005759" FT VARIANT 167 FT /note="R -> G (in VHLD; type I-II; dbSNP:rs5030820)" FT /evidence="ECO:0000269|PubMed:9829911" FT /id="VAR_005760" FT VARIANT 167 FT /note="R -> Q (in pheochromocytoma and VHLD; type II; FT common mutation; dbSNP:rs5030821)" FT /evidence="ECO:0000269|PubMed:12000816, FT ECO:0000269|PubMed:8956040, ECO:0000269|PubMed:9829912" FT /id="VAR_005761" FT VARIANT 167 FT /note="R -> W (in pheochromocytoma and VHLD; type II; FT common mutation; dbSNP:rs5030820)" FT /evidence="ECO:0000269|PubMed:12000816, FT ECO:0000269|PubMed:8592333, ECO:0000269|PubMed:8956040, FT ECO:0000269|PubMed:9829912" FT /id="VAR_005762" FT VARIANT 170 FT /note="V -> D (in VHLD; type II; dbSNP:rs864321642)" FT /evidence="ECO:0000269|PubMed:8730290" FT /id="VAR_005763" FT VARIANT 170 FT /note="V -> F (in VHLD; type II)" FT /id="VAR_005764" FT VARIANT 170 FT /note="V -> G (in VHLD; type I)" FT /evidence="ECO:0000269|PubMed:8956040, FT ECO:0000269|PubMed:9829912" FT /id="VAR_005765" FT VARIANT 175 FT /note="Y -> D (in VHLD; type I)" FT /evidence="ECO:0000269|PubMed:9829911" FT /id="VAR_005766" FT VARIANT 176 FT /note="R -> W (in VHLD)" FT /id="VAR_008104" FT VARIANT 177 FT /note="R -> RLRVKPE (in VHLD; type I)" FT /id="VAR_005767" FT VARIANT 178 FT /note="L -> P (in VHLD; type I-II; common mutation; FT dbSNP:rs5030822)" FT /evidence="ECO:0000269|PubMed:8956040" FT /id="VAR_005768" FT VARIANT 178 FT /note="L -> Q (in VHLD; type II; dbSNP:rs5030822)" FT /id="VAR_005769" FT VARIANT 180 FT /note="I -> V (in VHLD; type I; dbSNP:rs377715747)" FT /evidence="ECO:0000269|PubMed:8956040" FT /id="VAR_005770" FT VARIANT 184 FT /note="L -> P (in VHLD; type I; dbSNP:rs1064793878)" FT /evidence="ECO:0000269|PubMed:8956040, FT ECO:0000269|PubMed:9829911" FT /id="VAR_005772" FT VARIANT 184 FT /note="L -> R (in VHLD; type I)" FT /evidence="ECO:0000269|PubMed:8956040" FT /id="VAR_005771" FT VARIANT 186 FT /note="E -> K (in VHLD; type I; dbSNP:rs367545984)" FT /evidence="ECO:0000269|PubMed:8956040, FT ECO:0000269|PubMed:9829911" FT /id="VAR_005773" FT VARIANT 186 FT /note="Missing (in VHLD; dbSNP:rs1559429813)" FT /evidence="ECO:0000269|PubMed:8730290" FT /id="VAR_005774" FT VARIANT 188 FT /note="L -> P (in VHLD; type I-II; dbSNP:rs1559429824)" FT /evidence="ECO:0000269|PubMed:9829912" FT /id="VAR_005775" FT VARIANT 188 FT /note="L -> Q (in VHLD; type I; dbSNP:rs1559429824)" FT /evidence="ECO:0000269|PubMed:8956040" FT /id="VAR_005776" FT VARIANT 188 FT /note="L -> V (in ECYT2, pheochromocytoma and VHLD; type FT IIA; dbSNP:rs5030824)" FT /evidence="ECO:0000269|PubMed:12000816, FT ECO:0000269|PubMed:12844285" FT /id="VAR_005777" FT VARIANT 191 FT /note="H -> D (in ECYT2; dbSNP:rs28940301)" FT /evidence="ECO:0000269|PubMed:12844285" FT /id="VAR_034999" FT VARIANT 192 FT /note="P -> S (in ECYT2; dbSNP:rs28940300)" FT /evidence="ECO:0000269|PubMed:12844285" FT /id="VAR_035000" FT VARIANT 198 FT /note="L -> Q (in pheochromocytoma)" FT /evidence="ECO:0000269|PubMed:12000816" FT /id="VAR_035001" FT VARIANT 198 FT /note="L -> R (in ECYT2 and VHLD; type II)" FT /id="VAR_005778" FT VARIANT 200 FT /note="R -> W (in ECYT2 and VHLD; type I; FT dbSNP:rs28940298)" FT /evidence="ECO:0000269|PubMed:12393546, FT ECO:0000269|PubMed:12844285, ECO:0000269|PubMed:8956040, FT ECO:0000269|PubMed:9829912" FT /id="VAR_005779" FT MUTAGEN 98 FT /note="Y->N: No interaction with HIF1A. No HIF1A FT degradation." FT /evidence="ECO:0000269|PubMed:10944113" FT STRAND 62..64 FT /evidence="ECO:0007829|PDB:8BB5" FT STRAND 71..78 FT /evidence="ECO:0007829|PDB:7Z76" FT STRAND 80..82 FT /evidence="ECO:0007829|PDB:7Z76" FT STRAND 84..89 FT /evidence="ECO:0007829|PDB:7Z76" FT STRAND 91..93 FT /evidence="ECO:0007829|PDB:3ZTC" FT STRAND 95..97 FT /evidence="ECO:0007829|PDB:7Z76" FT STRAND 106..112 FT /evidence="ECO:0007829|PDB:7Z76" FT STRAND 116..121 FT /evidence="ECO:0007829|PDB:7Z76" FT TURN 122..124 FT /evidence="ECO:0007829|PDB:7Z76" FT STRAND 129..134 FT /evidence="ECO:0007829|PDB:6GMX" FT HELIX 142..144 FT /evidence="ECO:0007829|PDB:6GFX" FT STRAND 147..152 FT /evidence="ECO:0007829|PDB:7Z76" FT HELIX 158..169 FT /evidence="ECO:0007829|PDB:7Z76" FT HELIX 172..177 FT /evidence="ECO:0007829|PDB:7Z76" FT STRAND 178..180 FT /evidence="ECO:0007829|PDB:7Z76" FT HELIX 183..189 FT /evidence="ECO:0007829|PDB:7Z76" FT HELIX 194..201 FT /evidence="ECO:0007829|PDB:7Z76" FT HELIX 205..209 FT /evidence="ECO:0007829|PDB:8BDM" SQ SEQUENCE 213 AA; 24153 MW; BA5D6765FBC16EA7 CRC64; MPRRAENWDE AEVGAEEAGV EEYGPEEDGG EESGAEESGP EESGPEELGA EEEMEAGRPR PVLRSVNSRE PSQVIFCNRS PRVVLPVWLN FDGEPQPYPT LPPGTGRRIH SYRGHLWLFR DAGTHDGLLV NQTELFVPSL NVDGQPIFAN ITLPVYTLKE RCLQVVRSLV KPENYRRLDI VRSLYEDLED HPNVQKDLER LTQERIAHQR MGD //