ID KRIT1_HUMAN Reviewed; 736 AA. AC O00522; A6NNU0; O43894; Q506L6; Q6U276; Q75N19; Q9H180; Q9H264; Q9HAX5; DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot. DT 11-OCT-2005, sequence version 2. DT 27-MAR-2024, entry version 209. DE RecName: Full=Krev interaction trapped protein 1; DE Short=Krev interaction trapped 1; DE AltName: Full=Cerebral cavernous malformations 1 protein; GN Name=KRIT1; Synonyms=CCM1; 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], NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), RP TISSUE SPECIFICITY, AND INTERACTION WITH RAP1A. RC TISSUE=Kidney, and Mammary cancer; RX PubMed=9285558; DOI=10.1038/sj.onc.1201268; RA Serebriiskii I., Estojak J., Sonoda G., Testa J.R., Golemis E.A.; RT "Association of Krev-1/rap1a with Krit1, a novel ankyrin repeat-containing RT protein encoded by a gene mapping to 7q21-22."; RL Oncogene 15:1043-1049(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=11161791; DOI=10.1006/geno.2000.6410; RA Zhang J., Clatterbuck R.E., Rigamonti D., Dietz H.C.; RT "Cloning of the murine Krit1 cDNA reveals novel mammalian 5' coding RT exons."; RL Genomics 70:392-395(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND ALTERNATIVE SPLICING. RX PubMed=11161805; DOI=10.1006/geno.2000.6426; RA Sahoo T., Goenaga-Diaz E., Serebriiskii I.G., Thomas J.W., Kotova E., RA Cuellar J.G., Peloquin J.M., Golemis E., Beitinjaneh F., Green E.D., RA Johnson E.W., Marchuk D.A.; RT "Computational and experimental analyses reveal previously undetected RT coding exons of the KRIT1 (CCM1) gene."; RL Genomics 71:123-126(2001). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), ALTERNATIVE SPLICING, AND VARIANTS RP CCM1 SER-97 AND GLU-569. RX PubMed=12172908; DOI=10.1007/s00401-002-0552-6; RA Kehrer-Sawatzki H., Wilda M., Braun V.M., Richter H.-P., Hameister H.; RT "Mutation and expression analysis of the KRIT1 gene associated with RT cerebral cavernous malformations (CCM1)."; RL Acta Neuropathol. 104:231-240(2002). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Ferrera L., Marini V., Dorcaratto A., Pigatto F., Alberti F., Forni M., RA Cama A., Viale G., Origone P., Mareni C., Garre' C.; RT "Four novel and three known KRIT1 mutations in CCM Italian patients: RT Characterization at mRNA and protein level."; RL Submitted (SEP-2003) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Brain; 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 [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12853948; DOI=10.1038/nature01782; RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., RA Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., RA Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H., RA Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., RA Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., RA Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., RA Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., RA Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., RA Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., RA Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., RA Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., RA Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., RA Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., RA Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., RA Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., RA McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., RA Wilson R.K.; RT "The DNA sequence of human chromosome 7."; RL Nature 424:157-164(2003). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain, and Uterus; 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 [9] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-243, AND ALTERNATIVE SPLICING. RX PubMed=11342228; DOI=10.1016/s0167-4781(00)00303-1; RA Eerola I., McIntyre B., Vikkula M.; RT "Identification of eight novel 5`-exons in cerebral capillary malformation RT gene-1 (CCM1) encoding KRIT1."; RL Biochim. Biophys. Acta 1517:464-467(2001). RN [10] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 244-281. RA Marini V., Ferrera L., Dorcaratto A., Forni M., Capra V., Origone P., RA Mareni C., Garre' C.; RT "Six novel and three known KRIT1 mutations in CCM patients: RT characterization at mRNA level."; RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases. RN [11] RP FUNCTION, INTERACTION WITH ITGB1 AND ITGB1BP1, AND MUTAGENESIS OF ASN-192 RP AND TYR-195. RX PubMed=11741838; DOI=10.1093/hmg/10.25.2953; RA Zhang J., Clatterbuck R.E., Rigamonti D., Chang D.D., Dietz H.C.; RT "Interaction between krit1 and icap1alpha infers perturbation of integrin RT beta1-mediated angiogenesis in the pathogenesis of cerebral cavernous RT malformation."; RL Hum. Mol. Genet. 10:2953-2960(2001). RN [12] RP INTERACTION WITH ITGB1BP1, AND MUTAGENESIS OF ASN-192 AND TYR-195. RX PubMed=11854171; DOI=10.1093/hmg/11.4.389; RA Zawistowski J.S., Serebriiskii I.G., Lee M.F., Golemis E.A., Marchuk D.A.; RT "KRIT1 association with the integrin-binding protein ICAP-1: a new RT direction in the elucidation of cerebral cavernous malformations (CCM1) RT pathogenesis."; RL Hum. Mol. Genet. 11:389-396(2002). RN [13] RP FUNCTION, IDENTIFICATION IN A COMPLEX WITH ITGB1BP1 AND RAP1A, INTERACTION RP WITH ITGB1BP1 AND RAP1A, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP 47-LYS--LYS-50 AND 192-ASN--TYR-195. RX PubMed=17916086; DOI=10.1111/j.1742-4658.2007.06068.x; RA Beraud-Dufour S., Gautier R., Albiges-Rizo C., Chardin P., Faurobert E.; RT "Krit 1 interactions with microtubules and membranes are regulated by Rap1 RT and integrin cytoplasmic domain associated protein-1."; RL FEBS J. 274:5518-5532(2007). RN [14] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH CDH5. RX PubMed=20332120; DOI=10.1242/jcs.059329; RA Lampugnani M.G., Orsenigo F., Rudini N., Maddaluno L., Boulday G., RA Chapon F., Dejana E.; RT "CCM1 regulates vascular-lumen organization by inducing endothelial RT polarity."; RL J. Cell Sci. 123:1073-1080(2010). RN [15] RP FUNCTION. RX PubMed=20668652; DOI=10.1371/journal.pone.0011786; RA Goitre L., Balzac F., Degani S., Degan P., Marchi S., Pinton P., RA Retta S.F.; RT "KRIT1 regulates the homeostasis of intracellular reactive oxygen RT species."; RL PLoS ONE 5:E11786-E11786(2010). RN [16] RP FUNCTION. RX PubMed=20616044; DOI=10.1073/pnas.1000132107; RA Wuestehube J., Bartol A., Liebler S.S., Bruetsch R., Zhu Y., Felbor U., RA Sure U., Augustin H.G., Fischer A.; RT "Cerebral cavernous malformation protein CCM1 inhibits sprouting RT angiogenesis by activating DELTA-NOTCH signaling."; RL Proc. Natl. Acad. Sci. U.S.A. 107:12640-12645(2010). RN [17] RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH RAP1A, AND MUTAGENESIS OF RP ARG-452. RX PubMed=21633110; DOI=10.1091/mbc.e11-02-0157; RA Liu J.J., Stockton R.A., Gingras A.R., Ablooglu A.J., Han J., Bobkov A.A., RA Ginsberg M.H.; RT "A mechanism of Rap1-induced stabilization of endothelial cell--cell RT junctions."; RL Mol. Biol. Cell 22:2509-2519(2011). RN [18] RP FUNCTION. RX PubMed=26417067; DOI=10.15252/emmm.201505316; RA Marchi S., Corricelli M., Trapani E., Bravi L., Pittaro A., RA Delle Monache S., Ferroni L., Patergnani S., Missiroli S., Goitre L., RA Trabalzini L., Rimessi A., Giorgi C., Zavan B., Cassoni P., Dejana E., RA Retta S.F., Pinton P.; RT "Defective autophagy is a key feature of cerebral cavernous RT malformations."; RL EMBO Mol. Med. 7:1403-1417(2015). RN [19] RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 420-736 IN COMPLEX WITH RAP1B, RP MUTAGENESIS OF SER-430; ARG-432 AND ARG-452, AND INTERACTION WITH RAP1B. RX PubMed=22577140; DOI=10.1074/jbc.m112.361295; RA Li X., Zhang R., Draheim K.M., Liu W., Calderwood D.A., Boggon T.J.; RT "Structural basis for small G protein effector interaction of Ras-related RT protein 1 (Rap1) and adaptor protein Krev interaction trapped 1 (KRIT1)."; RL J. Biol. Chem. 287:22317-22327(2012). RN [20] RP X-RAY CRYSTALLOGRAPHY (2.49 ANGSTROMS) OF 417-736 IN COMPLEX WITH HEG1, RP INTERACTION WITH HEG1; RAP1A AND CCM2, SUBCELLULAR LOCATION, AND RP MUTAGENESIS OF LEU-717 AND LEU-721. RX PubMed=23007647; DOI=10.1083/jcb.201205109; RA Gingras A.R., Liu J.J., Ginsberg M.H.; RT "Structural basis of the junctional anchorage of the cerebral cavernous RT malformations complex."; RL J. Cell Biol. 199:39-48(2012). RN [21] RP X-RAY CRYSTALLOGRAPHY (2.54 ANGSTROMS) OF 1-198 IN COMPLEX WITH ITGB1BP1, RP INTERACTION WITH ITGB1BP1, FUNCTION, DOMAIN, AND MUTAGENESIS OF ALA-176; RP ARG-179; PRO-182; ARG-185; ASN-192 AND TYR-195. RX PubMed=23317506; DOI=10.1016/j.molcel.2012.12.005; RA Liu W., Draheim K.M., Zhang R., Calderwood D.A., Boggon T.J.; RT "Mechanism for KRIT1 release of ICAP1-mediated suppression of integrin RT activation."; RL Mol. Cell 49:719-729(2013). RN [22] {ECO:0007744|PDB:5D68} RP X-RAY CRYSTALLOGRAPHY (2.91 ANGSTROMS) OF 259-736, AND ANK REPEAT DOMAIN. RX PubMed=26458359; DOI=10.1016/j.jsb.2015.10.006; RA Zhang R., Li X., Boggon T.J.; RT "Structural analysis of the KRIT1 ankyrin repeat and FERM domains reveals a RT conformationally stable ARD-FERM interface."; RL J. Struct. Biol. 192:449-456(2015). CC -!- FUNCTION: Component of the CCM signaling pathway which is a crucial CC regulator of heart and vessel formation and integrity (By similarity). CC Negative regulator of angiogenesis. Inhibits endothelial proliferation, CC apoptosis, migration, lumen formation and sprouting angiogenesis in CC primary endothelial cells. Promotes AKT phosphorylation in a NOTCH- CC dependent and independent manner, and inhibits ERK1/2 phosphorylation CC indirectly through activation of the DELTA-NOTCH cascade. Acts in CC concert with CDH5 to establish and maintain correct endothelial cell CC polarity and vascular lumen and these effects are mediated by CC recruitment and activation of the Par polarity complex and RAP1B. CC Required for the localization of phosphorylated PRKCZ, PARD3, TIAM1 and CC RAP1B to the cell junction, and cell junction stabilization. Plays a CC role in integrin signaling via its interaction with ITGB1BP1; this CC prevents the interaction between ITGB1 and ITGB1BP1. Microtubule- CC associated protein that binds to phosphatidylinositol 4,5-bisphosphate CC (PIP2)-containing membranes in a GTP-bound RAP1-dependent manner. Plays CC an important role in the maintenance of the intracellular reactive CC oxygen species (ROS) homeostasis to prevent oxidative cellular damage. CC Regulates the homeostasis of intracellular ROS through an antioxidant CC pathway involving FOXO1 and SOD2. Facilitates the down-regulation of CC cyclin-D1 (CCND1) levels required for cell transition from CC proliferative growth to quiescence by preventing the accumulation of CC intracellular ROS through the modulation of FOXO1 and SOD2 levels. May CC play a role in the regulation of macroautophagy through the down- CC regulation of the mTOR pathway (PubMed:26417067). CC {ECO:0000250|UniProtKB:Q6S5J6, ECO:0000269|PubMed:11741838, CC ECO:0000269|PubMed:17916086, ECO:0000269|PubMed:20332120, CC ECO:0000269|PubMed:20616044, ECO:0000269|PubMed:20668652, CC ECO:0000269|PubMed:21633110, ECO:0000269|PubMed:23317506, CC ECO:0000269|PubMed:26417067}. CC -!- SUBUNIT: Interacts with CDH5 (PubMed:20332120). Found in a complex, at CC least composed of ITGB1BP1, KRIT1 and RAP1A. Interacts (via C-terminus CC FERM domain) with RAP1A (active GTP-bound form preferentially); the CC interaction does not induce the opening conformation of KRIT1. CC Interacts (via FERM domain) with RAP1B. Interacts (via N-terminus NPXY CC motif) with ITGB1BP1; the interaction induces the opening conformation CC of KRIT1 and competes with ITGB1 for ITGB1BP1 interaction. Interacts CC with HEG1 and CCM2; greatly facilitates CCM2-binding to HEG1. CC Associates (via N-terminus and C-terminus regions) with microtubules; CC the interaction is inhibited in presence of ITGB1BP1 and active GTP- CC bound RAP1A. {ECO:0000269|PubMed:11741838, ECO:0000269|PubMed:11854171, CC ECO:0000269|PubMed:17916086, ECO:0000269|PubMed:20332120, CC ECO:0000269|PubMed:21633110, ECO:0000269|PubMed:22577140, CC ECO:0000269|PubMed:23007647, ECO:0000269|PubMed:23317506, CC ECO:0000269|PubMed:9285558}. CC -!- INTERACTION: CC O00522; Q9BSQ5: CCM2; NbExp=15; IntAct=EBI-1573121, EBI-1573056; CC O00522; Q9BSQ5-1: CCM2; NbExp=2; IntAct=EBI-1573121, EBI-16157769; CC O00522; Q9ULI3: HEG1; NbExp=5; IntAct=EBI-1573121, EBI-12734419; CC O00522; O14713: ITGB1BP1; NbExp=4; IntAct=EBI-1573121, EBI-2127319; CC O00522; P61086: UBE2K; NbExp=3; IntAct=EBI-1573121, EBI-473850; CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton. Cell membrane; CC Peripheral membrane protein. Cell junction. Note=KRIT1 and CDH5 CC reciprocally regulate their localization to endothelial cell-cell CC junctions. Association with RAP1 relocalizes KRIT1 from microtubules to CC cell junction membranes. Translocates from the cytoplasm along CC microtubules to the cell membrane in a ITGB1BP1-dependent manner. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=O00522-1; Sequence=Displayed; CC Name=2; CC IsoId=O00522-2; Sequence=VSP_015800; CC Name=3; CC IsoId=O00522-3; Sequence=VSP_043327; CC -!- TISSUE SPECIFICITY: Low levels in brain. Very weak expression found in CC heart and muscle. {ECO:0000269|PubMed:9285558}. CC -!- DOMAIN: The FERM domain mediates binding to RAP1A and RAP1B and is CC necessary for binding to phosphatidylinositol 4,5-bisphosphate (PIP2). CC {ECO:0000269|PubMed:23317506}. CC -!- DOMAIN: The N-terminal domain has structural similarity to the nudix CC hydrolase domain, despite the absence of a nudix box and low sequence CC similarity with nudix hydrolase domains. The N-terminus and the C- CC terminus part associate together via the NPAY binding motif and adopt a CC lose conformation that is disrupted by ITGB1BP1, but not by RAP1A. CC {ECO:0000269|PubMed:23317506}. CC -!- DOMAIN: Contains 4 ANK repeats that precede the FERM domain. CC {ECO:0000269|PubMed:26458359}. CC -!- DISEASE: Cerebral cavernous malformations 1 (CCM1) [MIM:116860]: A form CC of cerebral cavernous malformations, a congenital vascular anomaly of CC the central nervous system that can result in hemorrhagic stroke, CC seizures, recurrent headaches, and focal neurologic deficits. The CC lesions are characterized by grossly enlarged blood vessels consisting CC of a single layer of endothelium and without any intervening neural CC tissue, ranging in diameter from a few millimeters to several CC centimeters. CCM1 inheritance is autosomal dominant. CC {ECO:0000269|PubMed:12172908}. Note=The disease is caused by variants CC affecting the gene represented in this entry. 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; U90268; AAB58582.1; -; mRNA. DR EMBL; U90269; AAC01535.1; -; Genomic_DNA. DR EMBL; AF310133; AAG47774.1; -; mRNA. DR EMBL; AF296765; AAG10220.2; -; mRNA. DR EMBL; AF388384; AAM19465.1; -; mRNA. DR EMBL; AY380057; AAQ94072.1; -; mRNA. DR EMBL; AK055305; BAG51497.1; -; mRNA. DR EMBL; AC000120; AAS07420.1; -; Genomic_DNA. DR EMBL; BC094684; AAH94684.1; -; mRNA. DR EMBL; BC098442; AAH98442.1; -; mRNA. DR EMBL; AJ294850; CAC17608.1; -; mRNA. DR EMBL; AY993945; AAY25568.1; -; Genomic_DNA. DR CCDS; CCDS34679.1; -. [O00522-3] DR CCDS; CCDS5624.1; -. [O00522-1] DR RefSeq; NP_001013424.1; NM_001013406.1. [O00522-3] DR RefSeq; NP_004903.2; NM_004912.3. [O00522-1] DR RefSeq; NP_919436.1; NM_194454.1. [O00522-1] DR RefSeq; NP_919437.1; NM_194455.1. [O00522-1] DR RefSeq; NP_919438.1; NM_194456.1. [O00522-1] DR RefSeq; XP_005250717.1; XM_005250660.3. DR RefSeq; XP_005250719.1; XM_005250662.3. DR RefSeq; XP_005250722.1; XM_005250665.3. DR RefSeq; XP_005250723.1; XM_005250666.3. DR RefSeq; XP_005250724.1; XM_005250667.2. DR RefSeq; XP_005250725.1; XM_005250668.3. DR RefSeq; XP_005250726.1; XM_005250669.3. DR RefSeq; XP_006716224.1; XM_006716161.3. DR RefSeq; XP_006716225.1; XM_006716162.3. DR RefSeq; XP_006716226.1; XM_006716163.3. DR RefSeq; XP_011514953.1; XM_011516651.2. DR RefSeq; XP_011514955.1; XM_011516653.2. DR RefSeq; XP_011514956.1; XM_011516654.2. DR RefSeq; XP_011514957.1; XM_011516655.2. DR RefSeq; XP_011514958.1; XM_011516656.2. DR RefSeq; XP_011514959.1; XM_011516657.2. DR RefSeq; XP_011514960.1; XM_011516658.2. DR RefSeq; XP_011514961.1; XM_011516659.2. DR RefSeq; XP_011514962.1; XM_011516660.2. DR RefSeq; XP_011514963.1; XM_011516661.2. DR RefSeq; XP_016868244.1; XM_017012755.1. DR RefSeq; XP_016868245.1; XM_017012756.1. DR RefSeq; XP_016868246.1; XM_017012757.1. DR PDB; 3U7D; X-ray; 2.49 A; A/C=417-736. DR PDB; 4DX8; X-ray; 2.54 A; H/I/J/K=1-198. DR PDB; 4DXA; X-ray; 1.95 A; B=420-736. DR PDB; 4HDO; X-ray; 1.67 A; A=417-736. DR PDB; 4HDQ; X-ray; 1.95 A; A=417-736. DR PDB; 4JIF; X-ray; 1.70 A; B=170-198. DR PDB; 4TKN; X-ray; 3.00 A; D/E/F=225-237. DR PDB; 5D68; X-ray; 2.91 A; A/B/C=259-736. DR PDB; 6OQ3; X-ray; 1.85 A; A=417-736. DR PDB; 6OQ4; X-ray; 1.75 A; A=417-736. DR PDB; 6UZK; X-ray; 1.92 A; A=417-736. DR PDB; 8SU8; X-ray; 2.01 A; A=419-736. DR PDB; 8T7V; X-ray; 2.25 A; A=417-736. DR PDBsum; 3U7D; -. DR PDBsum; 4DX8; -. DR PDBsum; 4DXA; -. DR PDBsum; 4HDO; -. DR PDBsum; 4HDQ; -. DR PDBsum; 4JIF; -. DR PDBsum; 4TKN; -. DR PDBsum; 5D68; -. DR PDBsum; 6OQ3; -. DR PDBsum; 6OQ4; -. DR PDBsum; 6UZK; -. DR PDBsum; 8SU8; -. DR PDBsum; 8T7V; -. DR AlphaFoldDB; O00522; -. DR SMR; O00522; -. DR BioGRID; 107330; 47. DR ComplexPortal; CPX-983; ICAP1-KRIT1 integrin activation complex. DR ComplexPortal; CPX-984; CCM endothelial permeability complex. DR CORUM; O00522; -. DR DIP; DIP-40610N; -. DR IntAct; O00522; 11. DR STRING; 9606.ENSP00000378015; -. DR iPTMnet; O00522; -. DR PhosphoSitePlus; O00522; -. DR BioMuta; KRIT1; -. DR EPD; O00522; -. DR jPOST; O00522; -. DR MassIVE; O00522; -. DR MaxQB; O00522; -. DR PaxDb; 9606-ENSP00000378015; -. DR PeptideAtlas; O00522; -. DR ProteomicsDB; 47953; -. [O00522-1] DR ProteomicsDB; 47954; -. [O00522-2] DR ProteomicsDB; 47955; -. [O00522-3] DR Pumba; O00522; -. DR Antibodypedia; 15587; 219 antibodies from 27 providers. DR DNASU; 889; -. DR Ensembl; ENST00000340022.6; ENSP00000344668.2; ENSG00000001631.17. [O00522-1] DR Ensembl; ENST00000394503.6; ENSP00000378011.2; ENSG00000001631.17. [O00522-3] DR Ensembl; ENST00000394505.7; ENSP00000378013.2; ENSG00000001631.17. [O00522-1] DR Ensembl; ENST00000394507.5; ENSP00000378015.1; ENSG00000001631.17. [O00522-1] DR Ensembl; ENST00000412043.6; ENSP00000410909.2; ENSG00000001631.17. [O00522-1] DR Ensembl; ENST00000425073.2; ENSP00000404790.2; ENSG00000001631.17. [O00522-1] DR Ensembl; ENST00000444960.6; ENSP00000388076.2; ENSG00000001631.17. [O00522-1] DR Ensembl; ENST00000458177.7; ENSP00000391675.2; ENSG00000001631.17. [O00522-1] DR Ensembl; ENST00000686094.1; ENSP00000510015.1; ENSG00000001631.17. [O00522-1] DR Ensembl; ENST00000686527.1; ENSP00000509139.1; ENSG00000001631.17. [O00522-1] DR Ensembl; ENST00000687135.1; ENSP00000509617.1; ENSG00000001631.17. [O00522-1] DR Ensembl; ENST00000688404.1; ENSP00000509939.1; ENSG00000001631.17. [O00522-1] DR Ensembl; ENST00000688665.1; ENSP00000509209.1; ENSG00000001631.17. [O00522-1] DR Ensembl; ENST00000689556.1; ENSP00000508543.1; ENSG00000001631.17. [O00522-3] DR Ensembl; ENST00000690529.1; ENSP00000510733.1; ENSG00000001631.17. [O00522-1] DR Ensembl; ENST00000690720.1; ENSP00000509832.1; ENSG00000001631.17. [O00522-1] DR Ensembl; ENST00000690908.1; ENSP00000510110.1; ENSG00000001631.17. [O00522-3] DR Ensembl; ENST00000692157.1; ENSP00000509514.1; ENSG00000001631.17. [O00522-1] DR Ensembl; ENST00000692807.1; ENSP00000508564.1; ENSG00000001631.17. [O00522-1] DR GeneID; 889; -. DR KEGG; hsa:889; -. DR MANE-Select; ENST00000394505.7; ENSP00000378013.2; NM_194454.3; NP_919436.1. DR UCSC; uc003ulr.2; human. [O00522-1] DR AGR; HGNC:1573; -. DR CTD; 889; -. DR DisGeNET; 889; -. DR GeneCards; KRIT1; -. DR GeneReviews; KRIT1; -. DR HGNC; HGNC:1573; KRIT1. DR HPA; ENSG00000001631; Low tissue specificity. DR MalaCards; KRIT1; -. DR MIM; 116860; phenotype. DR MIM; 604214; gene. DR neXtProt; NX_O00522; -. DR OpenTargets; ENSG00000001631; -. DR Orphanet; 221061; Familial cerebral cavernous malformation. DR PharmGKB; PA26144; -. DR VEuPathDB; HostDB:ENSG00000001631; -. DR eggNOG; KOG4335; Eukaryota. DR GeneTree; ENSGT00530000063721; -. DR HOGENOM; CLU_022188_0_0_1; -. DR InParanoid; O00522; -. DR OMA; ICELHIR; -. DR OrthoDB; 2876335at2759; -. DR PhylomeDB; O00522; -. DR TreeFam; TF317921; -. DR BioCyc; MetaCyc:ENSG00000001631-MONOMER; -. DR PathwayCommons; O00522; -. DR SignaLink; O00522; -. DR BioGRID-ORCS; 889; 14 hits in 1164 CRISPR screens. DR ChiTaRS; KRIT1; human. DR GeneWiki; KRIT1; -. DR GenomeRNAi; 889; -. DR Pharos; O00522; Tbio. DR PRO; PR:O00522; -. DR Proteomes; UP000005640; Chromosome 7. DR RNAct; O00522; Protein. DR Bgee; ENSG00000001631; Expressed in calcaneal tendon and 107 other cell types or tissues. DR ExpressionAtlas; O00522; baseline and differential. DR GO; GO:0005911; C:cell-cell junction; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-KW. DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell. DR GO; GO:0005615; C:extracellular space; HDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0032991; C:protein-containing complex; IEA:Ensembl. DR GO; GO:0030695; F:GTPase regulator activity; TAS:ProtInc. DR GO; GO:0008017; F:microtubule binding; IDA:UniProtKB. DR GO; GO:0005546; F:phosphatidylinositol-4,5-bisphosphate binding; IDA:UniProtKB. DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW. DR GO; GO:0045454; P:cell redox homeostasis; IMP:UniProtKB. DR GO; GO:0003158; P:endothelium development; NAS:ComplexPortal. DR GO; GO:0033622; P:integrin activation; IDA:ComplexPortal. DR GO; GO:0016525; P:negative regulation of angiogenesis; IMP:UniProtKB. DR GO; GO:2000352; P:negative regulation of endothelial cell apoptotic process; IMP:UniProtKB. DR GO; GO:0010596; P:negative regulation of endothelial cell migration; IMP:UniProtKB. DR GO; GO:0001937; P:negative regulation of endothelial cell proliferation; IMP:UniProtKB. DR GO; GO:0045765; P:regulation of angiogenesis; NAS:ComplexPortal. DR GO; GO:2000114; P:regulation of establishment of cell polarity; IMP:UniProtKB. DR GO; GO:0007264; P:small GTPase mediated signal transduction; TAS:ProtInc. DR CDD; cd14473; FERM_B-lobe; 1. DR CDD; cd13197; FERM_C_CCM1; 1. DR DisProt; DP01333; -. DR Gene3D; 1.20.80.10; -; 1. DR Gene3D; 1.25.40.20; Ankyrin repeat-containing domain; 1. DR Gene3D; 3.30.70.2240; KRIT, N-terminal Nudix domain, NPxY motif-rich region; 2. DR Gene3D; 2.30.29.30; Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB); 1. DR InterPro; IPR002110; Ankyrin_rpt. DR InterPro; IPR036770; Ankyrin_rpt-contain_sf. DR InterPro; IPR019749; Band_41_domain. DR InterPro; IPR014352; FERM/acyl-CoA-bd_prot_sf. DR InterPro; IPR035963; FERM_2. DR InterPro; IPR019748; FERM_central. DR InterPro; IPR000299; FERM_domain. DR InterPro; IPR041791; KRIT1_FERM_C. DR InterPro; IPR032022; NUDIX. DR InterPro; IPR043058; NUDIX_sf. DR InterPro; IPR011993; PH-like_dom_sf. DR PANTHER; PTHR13283; KREV INTERACTION TRAPPED 1-RELATED; 1. DR PANTHER; PTHR13283:SF11; KREV INTERACTION TRAPPED PROTEIN 1; 1. DR Pfam; PF13857; Ank_5; 1. DR Pfam; PF00373; FERM_M; 1. DR Pfam; PF16705; NUDIX_5; 1. DR SMART; SM00248; ANK; 3. DR SMART; SM00295; B41; 1. DR SUPFAM; SSF48403; Ankyrin repeat; 1. DR SUPFAM; SSF47031; Second domain of FERM; 1. DR PROSITE; PS50297; ANK_REP_REGION; 1. DR PROSITE; PS50088; ANK_REPEAT; 1. DR PROSITE; PS50057; FERM_3; 1. DR Genevisible; O00522; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Angiogenesis; ANK repeat; KW Cell junction; Cell membrane; Cytoplasm; Cytoskeleton; Disease variant; KW Membrane; Reference proteome; Repeat. FT CHAIN 1..736 FT /note="Krev interaction trapped protein 1" FT /id="PRO_0000067023" FT REPEAT 287..316 FT /note="ANK 1" FT /evidence="ECO:0000255" FT REPEAT 320..350 FT /note="ANK 2" FT /evidence="ECO:0000255" FT REPEAT 354..383 FT /note="ANK 3" FT /evidence="ECO:0000255" FT REPEAT 388..419 FT /note="ANK 4" FT /evidence="ECO:0000255" FT DOMAIN 420..734 FT /note="FERM" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00084" FT REGION 1..170 FT /note="N-terminal domain similar to Nudix hydrolase domain" FT REGION 172..195 FT /note="Interaction with ITGB1BP1" FT REGION 430..452 FT /note="Interaction with RAP1B" FT /evidence="ECO:0000269|PubMed:22577140" FT VAR_SEQ 1..207 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:9285558" FT /id="VSP_015800" FT VAR_SEQ 283..330 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_043327" FT VARIANT 97 FT /note="F -> S (in CCM1)" FT /evidence="ECO:0000269|PubMed:12172908" FT /id="VAR_023573" FT VARIANT 569 FT /note="K -> E (in CCM1)" FT /evidence="ECO:0000269|PubMed:12172908" FT /id="VAR_023574" FT MUTAGEN 47..50 FT /note="KKRK->AAAA: Reduces interaction with microtubules, FT but not with ITGB1BP1." FT /evidence="ECO:0000269|PubMed:17916086" FT MUTAGEN 176 FT /note="A->D: Strongly reduces ITGB1BP1 binding; when FT associated with D-182." FT /evidence="ECO:0000269|PubMed:23317506" FT MUTAGEN 179 FT /note="R->A: Strongly reduces ITGB1BP1 binding; when FT associated with A-179." FT /evidence="ECO:0000269|PubMed:23317506" FT MUTAGEN 182 FT /note="P->D: Strongly reduces ITGB1BP1 binding; when FT associated with D-176." FT /evidence="ECO:0000269|PubMed:23317506" FT MUTAGEN 185 FT /note="R->A: Strongly reduces ITGB1BP1 binding; when FT associated with A-179." FT /evidence="ECO:0000269|PubMed:23317506" FT MUTAGEN 192..195 FT /note="NPAY->APAA: Reduces interaction with ITGB1BP1." FT /evidence="ECO:0000269|PubMed:17916086" FT MUTAGEN 192 FT /note="N->A: Reduces ITGB1BP1 binding; when associated with FT A-195." FT /evidence="ECO:0000269|PubMed:11741838, FT ECO:0000269|PubMed:11854171, ECO:0000269|PubMed:23317506" FT MUTAGEN 195 FT /note="Y->A: Reduces ITGB1BP1 binding; when associated with FT A-192." FT /evidence="ECO:0000269|PubMed:11741838, FT ECO:0000269|PubMed:11854171, ECO:0000269|PubMed:23317506" FT MUTAGEN 430 FT /note="S->E: Impairs interaction with RAP1B." FT /evidence="ECO:0000269|PubMed:22577140" FT MUTAGEN 432 FT /note="R->E: Impairs interaction with RAP1B." FT /evidence="ECO:0000269|PubMed:22577140" FT MUTAGEN 452 FT /note="R->E: 40-fold-reduced affinity for Rap1A." FT /evidence="ECO:0000269|PubMed:21633110, FT ECO:0000269|PubMed:22577140" FT MUTAGEN 452 FT /note="R->E: Impairs interaction with RAP1B." FT /evidence="ECO:0000269|PubMed:21633110, FT ECO:0000269|PubMed:22577140" FT MUTAGEN 717 FT /note="L->A: Strongly reduced affinity for HEG1; when FT associated with A-721." FT /evidence="ECO:0000269|PubMed:23007647" FT MUTAGEN 721 FT /note="L->A: Strongly reduced affinity for HEG1; when FT associated with A-717." FT /evidence="ECO:0000269|PubMed:23007647" FT CONFLICT 138 FT /note="I -> T (in Ref. 5; AAQ94072)" FT /evidence="ECO:0000305" FT CONFLICT 234 FT /note="F -> G (in Ref. 1; AAB58582)" FT /evidence="ECO:0000305" FT CONFLICT 731 FT /note="P -> A (in Ref. 1; AAB58582, 2; AAG47774 and 5; FT AAQ94072)" FT /evidence="ECO:0000305" FT STRAND 9..17 FT /evidence="ECO:0007829|PDB:4DX8" FT HELIX 30..32 FT /evidence="ECO:0007829|PDB:4DX8" FT STRAND 33..39 FT /evidence="ECO:0007829|PDB:4DX8" FT STRAND 54..57 FT /evidence="ECO:0007829|PDB:4DX8" FT HELIX 64..75 FT /evidence="ECO:0007829|PDB:4DX8" FT STRAND 92..98 FT /evidence="ECO:0007829|PDB:4DX8" FT STRAND 107..114 FT /evidence="ECO:0007829|PDB:4DX8" FT STRAND 131..134 FT /evidence="ECO:0007829|PDB:4DX8" FT HELIX 135..141 FT /evidence="ECO:0007829|PDB:4DX8" FT HELIX 151..170 FT /evidence="ECO:0007829|PDB:4DX8" FT HELIX 173..178 FT /evidence="ECO:0007829|PDB:4DX8" FT HELIX 182..185 FT /evidence="ECO:0007829|PDB:4JIF" FT STRAND 186..191 FT /evidence="ECO:0007829|PDB:4JIF" FT HELIX 193..195 FT /evidence="ECO:0007829|PDB:4JIF" FT TURN 232..235 FT /evidence="ECO:0007829|PDB:4TKN" FT HELIX 291..297 FT /evidence="ECO:0007829|PDB:5D68" FT HELIX 301..309 FT /evidence="ECO:0007829|PDB:5D68" FT HELIX 324..330 FT /evidence="ECO:0007829|PDB:5D68" FT HELIX 334..342 FT /evidence="ECO:0007829|PDB:5D68" FT HELIX 358..364 FT /evidence="ECO:0007829|PDB:5D68" FT HELIX 368..376 FT /evidence="ECO:0007829|PDB:5D68" FT HELIX 392..399 FT /evidence="ECO:0007829|PDB:5D68" FT HELIX 404..412 FT /evidence="ECO:0007829|PDB:5D68" FT STRAND 415..417 FT /evidence="ECO:0007829|PDB:5D68" FT STRAND 421..425 FT /evidence="ECO:0007829|PDB:4HDO" FT STRAND 431..435 FT /evidence="ECO:0007829|PDB:4HDO" FT HELIX 439..441 FT /evidence="ECO:0007829|PDB:4HDO" FT HELIX 444..449 FT /evidence="ECO:0007829|PDB:4HDO" FT HELIX 455..458 FT /evidence="ECO:0007829|PDB:4HDO" FT STRAND 461..467 FT /evidence="ECO:0007829|PDB:4HDO" FT STRAND 470..473 FT /evidence="ECO:0007829|PDB:4HDO" FT HELIX 480..485 FT /evidence="ECO:0007829|PDB:4HDO" FT HELIX 487..494 FT /evidence="ECO:0007829|PDB:4HDO" FT HELIX 499..501 FT /evidence="ECO:0007829|PDB:4HDO" FT STRAND 505..510 FT /evidence="ECO:0007829|PDB:4HDO" FT HELIX 516..519 FT /evidence="ECO:0007829|PDB:4HDO" FT HELIX 525..541 FT /evidence="ECO:0007829|PDB:4HDO" FT HELIX 548..563 FT /evidence="ECO:0007829|PDB:4HDO" FT HELIX 568..571 FT /evidence="ECO:0007829|PDB:4HDO" FT STRAND 572..574 FT /evidence="ECO:0007829|PDB:4HDO" FT HELIX 578..581 FT /evidence="ECO:0007829|PDB:4HDO" FT TURN 582..584 FT /evidence="ECO:0007829|PDB:4HDO" FT HELIX 587..589 FT /evidence="ECO:0007829|PDB:4HDO" FT TURN 590..593 FT /evidence="ECO:0007829|PDB:4HDO" FT HELIX 594..596 FT /evidence="ECO:0007829|PDB:4HDO" FT HELIX 598..610 FT /evidence="ECO:0007829|PDB:4HDO" FT STRAND 612..614 FT /evidence="ECO:0007829|PDB:6UZK" FT HELIX 618..629 FT /evidence="ECO:0007829|PDB:4HDO" FT TURN 633..636 FT /evidence="ECO:0007829|PDB:4HDO" FT STRAND 638..645 FT /evidence="ECO:0007829|PDB:4HDO" FT TURN 650..652 FT /evidence="ECO:0007829|PDB:4HDQ" FT STRAND 655..662 FT /evidence="ECO:0007829|PDB:4HDO" FT STRAND 664..671 FT /evidence="ECO:0007829|PDB:4HDO" FT TURN 672..674 FT /evidence="ECO:0007829|PDB:4HDO" FT STRAND 677..682 FT /evidence="ECO:0007829|PDB:4HDO" FT STRAND 685..690 FT /evidence="ECO:0007829|PDB:4HDO" FT STRAND 694..701 FT /evidence="ECO:0007829|PDB:4HDO" FT TURN 702..705 FT /evidence="ECO:0007829|PDB:4HDO" FT STRAND 706..711 FT /evidence="ECO:0007829|PDB:4HDO" FT HELIX 715..728 FT /evidence="ECO:0007829|PDB:4HDO" SQ SEQUENCE 736 AA; 84348 MW; D11F75ED629E85AC CRC64; MGNPENIEDA YVAVIRPKNT ASLNSREYRA KSYEILLHEV PIEGQKKKRK KVLLETKLQG NSEITQGILD YVVETTKPIS PANQGIRGKR VVLMKKFPLD GEKMGREASL FIVPSVVKDN TKYTYTPGCP IFYCLQDIMR VCSESSTHFA TLTARMLIAL DKWLDERHAQ SHFIPALFRP SPLERIKTNV INPAYATESG QTENSLHMGY SALEIKSKML ALEKADTCIY NPLFGSDLQY TNRVDKVVIN PYFGLGAPDY SKIQIPKQEK WQRSMSSVTE DKERQWVDDF PLHRSACEGD SELLSRLLSE RFSVNQLDSD HWAPIHYACW YGKVEATRIL LEKGKCNPNL LNGQLSSPLH FAAGGGHAEI VQILLNHPET DRHITDQQGR SPLNICEENK QNNWEEAAKL LKEAINKPYE KVRIYRMDGS YRSVELKHGN NTTVQQIMEG MRLSQETQQY FTIWICSENL SLQLKPYHKP LQHVRDWPEI LAELTNLDPQ RETPQLFLRR DVRLPLEVEK QIEDPLAILI LFDEARYNLL KGFYTAPDAK LITLASLLLQ IVYGNYESKK HKQGFLNEEN LKSIVPVTKL KSKAPHWTNR ILHEYKNLST SEGVSKEMHH LQRMFLQNCW EIPTYGAAFF TGQIFTKASP SNHKVIPVYV GVNIKGLHLL NMETKALLIS LKYGCFMWQL GDTDTCFQIH SMENKMSFIV HTKQAGLVVK LLMKLNGQLM PTERNS //