ID UHRF1_MOUSE Reviewed; 782 AA. AC Q8VDF2; Q3U9D7; Q3U9P2; Q3UI74; Q3UIE6; Q3ULF2; Q3ULQ0; Q8C6F1; Q8VIA1; AC Q9Z1H6; DT 07-JUN-2005, integrated into UniProtKB/Swiss-Prot. DT 07-JUN-2005, sequence version 2. DT 27-MAR-2024, entry version 197. DE RecName: Full=E3 ubiquitin-protein ligase UHRF1; DE EC=2.3.2.27; DE AltName: Full=Nuclear protein 95; DE AltName: Full=Nuclear zinc finger protein Np95; DE AltName: Full=RING-type E3 ubiquitin transferase UHRF1; DE AltName: Full=Ubiquitin-like PHD and RING finger domain-containing protein 1; DE Short=mUhrf1; DE AltName: Full=Ubiquitin-like-containing PHD and RING finger domains protein 1; GN Name=Uhrf1; Synonyms=Np95; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY. RC TISSUE=T lymphoblast; RX PubMed=9880673; DOI=10.1007/s003359900920; RA Fujimori A., Matsuda Y., Takemoto Y., Hashimoto Y., Kubo E., Araki R., RA Fukumura R., Mita K., Tatsumi K., Muto M.; RT "Cloning and mapping of Np95 gene which encodes a novel nuclear protein RT associated with cell proliferation."; RL Mamm. Genome 9:1032-1035(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Davenport J.W., Fernandes E.R., Neale G.A.M., Goorha R.M.; RT "LMO2-induced T cell leukemias overexpress Np95, a gene containing RING and RT PHD zinc fingers and an ubiquitin-like domain."; RL Submitted (JUN-2000) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC STRAIN=C57BL/6J; RC TISSUE=Bone marrow, Heart, Small intestine, Spleen, and Stomach; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=C57BL/6J; RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112; RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S., RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., RA Eichler E.E., Ponting C.P.; RT "Lineage-specific biology revealed by a finished genome assembly of the RT mouse."; RL PLoS Biol. 7:E1000112-E1000112(2009). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC STRAIN=Czech II; TISSUE=Mammary tumor; 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 1-474, FUNCTION IN DNA REPAIR, AND RP DISRUPTION PHENOTYPE. RX PubMed=12084726; DOI=10.1074/jbc.m205189200; RA Muto M., Kanari Y., Kubo E., Takabe T., Kurihara T., Fujimori A., RA Tatsumi K.; RT "Targeted disruption of Np95 gene renders murine embryonic stem cells RT hypersensitive to DNA damaging agents and DNA replication blocks."; RL J. Biol. Chem. 277:34549-34555(2002). RN [7] RP SUBCELLULAR LOCATION, AND INDUCTION. RX PubMed=8634372; DOI=10.1111/j.1365-2184.1995.tb00051.x; RA Muto M., Utsuyama M., Horiguchi T., Kubo E., Sado T., Hirokawa K.; RT "The characterization of the monoclonal antibody Th-10a, specific for a RT nuclear protein appearing in the S phase of the cell cycle in normal RT thymocytes and its unregulated expression in lymphoma cell lines."; RL Cell Prolif. 28:645-657(1995). RN [8] RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INDUCTION. RX PubMed=10984098; DOI=10.1247/csf.25.149; RA Uemura T., Kubo E., Kanari Y., Ikemura T., Tatsumi K., Muto M.; RT "Temporal and spatial localization of novel nuclear protein NP95 in mitotic RT and meiotic cells."; RL Cell Struct. Funct. 25:149-159(2000). RN [9] RP SUBCELLULAR LOCATION, AND INDUCTION. RX PubMed=11161719; DOI=10.1006/excr.2000.5115; RA Miura M., Watanabe H., Sasaki T., Tatsumi K., Muto M.; RT "Dynamic changes in subnuclear NP95 location during the cell cycle and its RT spatial relationship with DNA replication foci."; RL Exp. Cell Res. 263:202-208(2001). RN [10] RP FUNCTION, AND INDUCTION. RX PubMed=12058012; DOI=10.1083/jcb.200201025; RA Bonapace I.M., Latella L., Papait R., Nicassio F., Sacco A., Muto M., RA Crescenzi M., Di Fiore P.P.; RT "Np95 is regulated by E1A during mitotic reactivation of terminally RT differentiated cells and is essential for S phase entry."; RL J. Cell Biol. 157:909-914(2002). RN [11] RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF HIS-730. RX PubMed=14993289; DOI=10.1128/mcb.24.6.2526-2535.2004; RA Citterio E., Papait R., Nicassio F., Vecchi M., Gomiero P., Mantovani R., RA Di Fiore P.P., Bonapace I.M.; RT "Np95 is a histone-binding protein endowed with ubiquitin ligase RT activity."; RL Mol. Cell. Biol. 24:2526-2535(2004). RN [12] RP FUNCTION, AND INTERACTION WITH HDAC1. RX PubMed=15361834; DOI=10.1038/sj.onc.1208053; RA Unoki M., Nishidate T., Nakamura Y.; RT "ICBP90, an E2F-1 target, recruits HDAC1 and binds to methyl-CpG through RT its SRA domain."; RL Oncogene 23:7601-7610(2004). RN [13] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH DNMT1. RX PubMed=17994007; DOI=10.1038/nature06397; RA Sharif J., Muto M., Takebayashi S., Suetake I., Iwamatsu A., Endo T.A., RA Shinga J., Mizutani-Koseki Y., Toyoda T., Okamura K., Tajima S., RA Mitsuya K., Okano M., Koseki H.; RT "The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 RT to methylated DNA."; RL Nature 450:908-912(2007). RN [14] RP FUNCTION. RX PubMed=17673620; DOI=10.1126/science.1147939; RA Bostick M., Kim J.K., Esteve P.O., Clark A., Pradhan S., Jacobsen S.E.; RT "UHRF1 plays a role in maintaining DNA methylation in mammalian cells."; RL Science 317:1760-1764(2007). RN [15] RP INTERACTION WITH DNMT3A AND DNMT3B. RX PubMed=19798101; DOI=10.1038/embor.2009.201; RA Meilinger D., Fellinger K., Bultmann S., Rothbauer U., Bonapace I.M., RA Klinkert W.E., Spada F., Leonhardt H.; RT "Np95 interacts with de novo DNA methyltransferases, Dnmt3a and Dnmt3b, and RT mediates epigenetic silencing of the viral CMV promoter in embryonic stem RT cells."; RL EMBO Rep. 10:1259-1264(2009). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-656, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19144319; DOI=10.1016/j.immuni.2008.11.006; RA Trost M., English L., Lemieux S., Courcelles M., Desjardins M., RA Thibault P.; RT "The phagosomal proteome in interferon-gamma-activated macrophages."; RL Immunity 30:143-154(2009). RN [17] RP INTERACTION WITH EHMT2. RX PubMed=19056828; DOI=10.1093/nar/gkn961; RA Kim J.K., Esteve P.O., Jacobsen S.E., Pradhan S.; RT "UHRF1 binds G9a and participates in p21 transcriptional regulation in RT mammalian cells."; RL Nucleic Acids Res. 37:493-505(2009). RN [18] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-161 AND SER-519, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Lung, and Spleen; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). RN [19] RP DNA-BINDING. RX PubMed=20026581; DOI=10.1093/nar/gkp1152; RA Rottach A., Frauer C., Pichler G., Bonapace I.M., Spada F., Leonhardt H.; RT "The multi-domain protein Np95 connects DNA methylation and histone RT modification."; RL Nucleic Acids Res. 38:1796-1804(2010). RN [20] RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF PHE-148. RX PubMed=21489993; DOI=10.1074/jbc.m111.234104; RA Nady N., Lemak A., Walker J.R., Avvakumov G.V., Kareta M.S., Achour M., RA Xue S., Duan S., Allali-Hassani A., Zuo X., Wang Y.X., Bronner C., RA Chedin F., Arrowsmith C.H., Dhe-Paganon S.; RT "Recognition of multivalent histone states associated with heterochromatin RT by UHRF1 protein."; RL J. Biol. Chem. 286:24300-24311(2011). RN [21] RP FUNCTION, AUTOUBIQUITINATION, DEUBIQUITINATION BY USP7, AND INTERACTION RP WITH USP7 AND DNMT1. RX PubMed=21268065; DOI=10.1002/jcb.22998; RA Qin W., Leonhardt H., Spada F.; RT "Usp7 and Uhrf1 control ubiquitination and stability of the maintenance DNA RT methyltransferase Dnmt1."; RL J. Cell. Biochem. 112:439-444(2011). RN [22] RP INTERACTION WITH PRAMEL7. RX PubMed=28604677; DOI=10.1038/ncb3554; RA Graf U., Casanova E.A., Wyck S., Dalcher D., Gatti M., Vollenweider E., RA Okoniewski M.J., Weber F.A., Patel S.S., Schmid M.W., Li J., Sharif J., RA Wanner G.A., Koseki H., Wong J., Pelczar P., Penengo L., Santoro R., RA Cinelli P.; RT "Pramel7 mediates ground-state pluripotency through proteasomal-epigenetic RT combined pathways."; RL Nat. Cell Biol. 19:763-773(2017). RN [23] RP INTERACTION WITH TET1, AND SUBCELLULAR LOCATION. RX PubMed=36056023; DOI=10.1038/s41467-022-32799-8; RA Arroyo M., Hastert F.D., Zhadan A., Schelter F., Zimbelmann S., Rausch C., RA Ludwig A.K., Carell T., Cardoso M.C.; RT "Isoform-specific and ubiquitination dependent recruitment of Tet1 to RT replicating heterochromatin modulates methylcytosine oxidation."; RL Nat. Commun. 13:5173-5173(2022). RN [24] RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 405-613 IN COMPLEX WITH RP HEMIMETHYLATED DNA. RX PubMed=18772891; DOI=10.1038/nature07249; RA Arita K., Ariyoshi M., Tochio H., Nakamura Y., Shirakawa M.; RT "Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base- RT flipping mechanism."; RL Nature 455:818-821(2008). RN [25] RP X-RAY CRYSTALLOGRAPHY (2.19 ANGSTROMS) OF 419-628 IN COMPLEX WITH RP HEMIMETHYLATED DNA. RX PubMed=18772888; DOI=10.1038/nature07280; RA Hashimoto H., Horton J.R., Zhang X., Bostick M., Jacobsen S.E., Cheng X.; RT "The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix."; RL Nature 455:826-829(2008). RN [26] RP X-RAY CRYSTALLOGRAPHY (1.99 ANGSTROMS) OF 417-628. RX PubMed=19077538; DOI=10.4161/epi.4.1.7370; RA Hashimoto H., Horton J.R., Zhang X., Cheng X.; RT "UHRF1, a modular multi-domain protein, regulates replication-coupled RT crosstalk between DNA methylation and histone modifications."; RL Epigenetics 4:8-14(2009). CC -!- FUNCTION: Multidomain protein that acts as a key epigenetic regulator CC by bridging DNA methylation and chromatin modification. Specifically CC recognizes and binds hemimethylated DNA at replication forks via its CC YDG domain and recruits DNMT1 methyltransferase to ensure faithful CC propagation of the DNA methylation patterns through DNA replication. In CC addition to its role in maintenance of DNA methylation, also plays a CC key role in chromatin modification: through its tudor-like regions and CC PHD-type zinc fingers, specifically recognizes and binds histone H3 CC trimethylated at 'Lys-9' (H3K9me3) and unmethylated at 'Arg-2' CC (H3R2me0), respectively, and recruits chromatin proteins. Enriched in CC pericentric heterochromatin where it recruits different chromatin CC modifiers required for this chromatin replication. Also localizes to CC euchromatic regions where it negatively regulates transcription CC possibly by impacting DNA methylation and histone modifications. Has E3 CC ubiquitin-protein ligase activity by mediating the ubiquitination of CC target proteins such as histone H3 and PML. It is still unclear how E3 CC ubiquitin-protein ligase activity is related to its role in chromatin CC in vivo. Plays a role in DNA repair by cooperating with UHRF2 to ensure CC recruitment of FANCD2 to interstrand cross-links (ICLs) leading to CC FANCD2 activation. Plays a pivotal role in the establishment of correct CC spindle architecture by catalyzing the 'Lys-63'-linked ubiquitination CC of KIF11, thereby controlling KIF11 localization on the spindle. CC {ECO:0000250|UniProtKB:Q96T88, ECO:0000269|PubMed:12058012, CC ECO:0000269|PubMed:12084726, ECO:0000269|PubMed:14993289, CC ECO:0000269|PubMed:15361834, ECO:0000269|PubMed:17673620, CC ECO:0000269|PubMed:17994007, ECO:0000269|PubMed:21268065, CC ECO:0000269|PubMed:21489993}. CC -!- CATALYTIC ACTIVITY: CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L- CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.; CC EC=2.3.2.27; Evidence={ECO:0000250|UniProtKB:Q96T88}; CC -!- PATHWAY: Protein modification; protein ubiquitination. CC -!- SUBUNIT: Interacts with DNMT3A and DNMT3B. Interacts with DNMT1; the CC interaction is direct. Interacts with USP7; leading to its CC deubiquitination. Interacts with HDAC1, but not with HDAC2. Interacts CC with BLTP3A. Interacts with PML. Interacts with EHMT2. Binds CC hemimethylated CpG containing oligonucleotides (PubMed:15361834, CC PubMed:17994007, PubMed:18772888, PubMed:18772891, PubMed:19056828, CC PubMed:19798101, PubMed:21268065). Interacts with PRAMEL7 CC (PubMed:28604677). Interacts with ZNF263; recruited to the SIX3 CC promoter along with other proteins involved in chromatin modification CC and transcriptional corepression where it contributes to CC transcriptional repression (By similarity). Interacts with UHRF2 (By CC similarity). Interacts with FANCD2 (By similarity). Interacts with TET1 CC isoform 2; this interaction induces the recruitment of TET1 isoform 2 CC to replicating heterochromatin (PubMed:36056023). CC {ECO:0000250|UniProtKB:Q96T88, ECO:0000269|PubMed:14993289, CC ECO:0000269|PubMed:15361834, ECO:0000269|PubMed:17994007, CC ECO:0000269|PubMed:18772888, ECO:0000269|PubMed:18772891, CC ECO:0000269|PubMed:19056828, ECO:0000269|PubMed:19798101, CC ECO:0000269|PubMed:21268065, ECO:0000269|PubMed:28604677, CC ECO:0000269|PubMed:36056023}. CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00358, CC ECO:0000269|PubMed:10984098, ECO:0000269|PubMed:11161719, CC ECO:0000269|PubMed:14993289, ECO:0000269|PubMed:17994007, CC ECO:0000269|PubMed:21489993, ECO:0000269|PubMed:36056023, CC ECO:0000269|PubMed:8634372}. Note=Associated, through the YDG domain CC (also called SRA domain), with replicating DNA from early to late S CC phase, including at replicating pericentric heterochromatin CC (PubMed:36056023). Also localizes to euchromatic regions. In non-S- CC phase cells, homogenously distributed through the nucleus CC (PubMed:36056023). {ECO:0000269|PubMed:36056023}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q8VDF2-1; Sequence=Displayed; CC Name=2; CC IsoId=Q8VDF2-2; Sequence=VSP_044395; CC -!- TISSUE SPECIFICITY: Expressed in thymus, testis, spleen and lung. CC Within testis, expressed in almost all cells except elongated CC spermatids. {ECO:0000269|PubMed:10984098, ECO:0000269|PubMed:9880673}. CC -!- INDUCTION: Up-regulated in proliferating cells, and down-regulated in CC quiescent or differentiated cells. Early induced by E1A in postmitotic CC cells. Down-regulated by aphidicolin. {ECO:0000269|PubMed:10984098, CC ECO:0000269|PubMed:11161719, ECO:0000269|PubMed:12058012, CC ECO:0000269|PubMed:8634372}. CC -!- DOMAIN: The tudor-like regions specifically recognize and bind histone CC H3 unmethylated at 'Arg-2' (H3R2me0), while the PHD-type zinc finger CC specifically recognizes and binds histone H3 trimethylated at 'Lys-9' CC (H3K9me3). The tudor-like regions simultaneously recognizes H3K9me3 CC through a conserved aromatic cage in the first tudor-like subdomain and CC unmodified H3K4 (H3K4me0) within a groove between the tandem subdomains CC (PubMed:21489993). The linker region plays a role in the formation of a CC histone H3-binding hole between the reader modules formed by the tudor- CC like regions and the PHD-type zinc finger by making extended contacts CC with the tandem tudor-like regions. {ECO:0000269|PubMed:21489993}. CC -!- DOMAIN: The YDG domain (also named SRA domain) specifically recognizes CC and binds hemimethylated DNA at replication forks (DNA that is only CC methylated on the mother strand of replicating DNA) (PubMed:17994007). CC The YDG domain contains a binding pocket that accommodates the 5- CC methylcytosine that is flipped out of the duplex DNA. 2 specialized CC loops reach through the resulting gap in the DNA from both the major CC and the minor grooves to read the other 3 bases of the CpG duplex. The CC major groove loop confers both specificity for the CpG dinucleotide and CC discrimination against methylation of deoxycytidine of the CC complementary strand (PubMed:18772888). The YDG domain also recognizes CC and binds 5-hydroxymethylcytosine (5hmC). {ECO:0000269|PubMed:17994007, CC ECO:0000269|PubMed:18772888}. CC -!- DOMAIN: The RING finger is required for ubiquitin ligase activity. CC -!- PTM: Phosphorylation at Ser-303 of the linker region decreases the CC binding to H3K9me3. Phosphorylation at Ser-639 by CDK1 during M phase CC impairs interaction with USP7, preventing deubiquitination and leading CC to degradation by the proteasome (By similarity). {ECO:0000250}. CC -!- PTM: Ubiquitinated; which leads to proteasomal degradation. CC Autoubiquitinated; interaction with USP7 leads to deubiquitination and CC prevents degradation. Ubiquitination and degradation takes place during CC M phase, when phosphorylation at Ser-639 prevents interaction with USP7 CC and subsequent deubiquitination. Polyubiquitination may be stimulated CC by DNA damage. {ECO:0000269|PubMed:21268065}. CC -!- DISRUPTION PHENOTYPE: Mice display a sensitization to DNA damage and CC replication block, and die in mid-gestation. CC {ECO:0000269|PubMed:12084726}. 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; D87908; BAA74579.1; -; mRNA. DR EMBL; AF274046; AAK55743.1; -; mRNA. DR EMBL; AK075819; BAC35985.1; -; mRNA. DR EMBL; AK143688; BAE25499.1; -; mRNA. DR EMBL; AK145376; BAE26398.1; -; mRNA. DR EMBL; AK145543; BAE26496.1; -; mRNA. DR EMBL; AK146951; BAE27560.1; -; mRNA. DR EMBL; AK147046; BAE27632.1; -; mRNA. DR EMBL; AK150489; BAE29605.1; -; mRNA. DR EMBL; AK151701; BAE30624.1; -; mRNA. DR EMBL; AK151837; BAE30730.1; -; mRNA. DR EMBL; AK152930; BAE31605.1; -; mRNA. DR EMBL; AK153083; BAE31708.1; -; mRNA. DR EMBL; AC026385; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC022167; AAH22167.1; -; mRNA. DR EMBL; AB066246; BAB79496.1; -; Genomic_DNA. DR CCDS; CCDS28903.1; -. [Q8VDF2-1] DR CCDS; CCDS50151.1; -. [Q8VDF2-2] DR RefSeq; NP_001104548.1; NM_001111078.1. [Q8VDF2-1] DR RefSeq; NP_001104549.1; NM_001111079.1. [Q8VDF2-2] DR RefSeq; NP_001104550.1; NM_001111080.1. [Q8VDF2-2] DR RefSeq; NP_035061.3; NM_010931.3. [Q8VDF2-1] DR PDB; 2ZKD; X-ray; 1.60 A; A/B=404-613. DR PDB; 2ZKE; X-ray; 2.60 A; A=404-613. DR PDB; 2ZKF; X-ray; 2.55 A; A=404-613. DR PDB; 2ZKG; X-ray; 1.77 A; A/B/C/D=404-613. DR PDB; 2ZO0; X-ray; 2.19 A; B=419-628. DR PDB; 2ZO1; X-ray; 1.96 A; B=419-628. DR PDB; 2ZO2; X-ray; 3.09 A; B=419-628. DR PDB; 3F8I; X-ray; 2.29 A; A/B=419-628. DR PDB; 3F8J; X-ray; 1.99 A; B=417-628. DR PDB; 3FDE; X-ray; 1.41 A; A/B=419-628. DR PDB; 6M2V; X-ray; 3.00 A; A/B=417-628. DR PDB; 6VEE; NMR; -; A=122-305. DR PDB; 6VFO; NMR; -; A=303-380. DR PDB; 7XGA; NMR; -; A=304-372. DR PDBsum; 2ZKD; -. DR PDBsum; 2ZKE; -. DR PDBsum; 2ZKF; -. DR PDBsum; 2ZKG; -. DR PDBsum; 2ZO0; -. DR PDBsum; 2ZO1; -. DR PDBsum; 2ZO2; -. DR PDBsum; 3F8I; -. DR PDBsum; 3F8J; -. DR PDBsum; 3FDE; -. DR PDBsum; 6M2V; -. DR PDBsum; 6VEE; -. DR PDBsum; 6VFO; -. DR PDBsum; 7XGA; -. DR AlphaFoldDB; Q8VDF2; -. DR SMR; Q8VDF2; -. DR BioGRID; 201816; 35. DR MINT; Q8VDF2; -. DR STRING; 10090.ENSMUSP00000001258; -. DR GlyGen; Q8VDF2; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q8VDF2; -. DR PhosphoSitePlus; Q8VDF2; -. DR SwissPalm; Q8VDF2; -. DR REPRODUCTION-2DPAGE; Q8VDF2; -. DR EPD; Q8VDF2; -. DR jPOST; Q8VDF2; -. DR MaxQB; Q8VDF2; -. DR PaxDb; 10090-ENSMUSP00000001258; -. DR PeptideAtlas; Q8VDF2; -. DR ProteomicsDB; 298473; -. [Q8VDF2-1] DR ProteomicsDB; 298474; -. [Q8VDF2-2] DR Pumba; Q8VDF2; -. DR Antibodypedia; 72541; 480 antibodies from 34 providers. DR DNASU; 18140; -. DR Ensembl; ENSMUST00000001258.15; ENSMUSP00000001258.9; ENSMUSG00000001228.15. [Q8VDF2-1] DR Ensembl; ENSMUST00000113035.8; ENSMUSP00000108658.2; ENSMUSG00000001228.15. [Q8VDF2-2] DR Ensembl; ENSMUST00000113038.8; ENSMUSP00000108661.2; ENSMUSG00000001228.15. [Q8VDF2-2] DR Ensembl; ENSMUST00000113039.9; ENSMUSP00000108662.3; ENSMUSG00000001228.15. [Q8VDF2-1] DR GeneID; 18140; -. DR KEGG; mmu:18140; -. DR UCSC; uc008dbp.2; mouse. [Q8VDF2-1] DR UCSC; uc008dbq.2; mouse. [Q8VDF2-2] DR AGR; MGI:1338889; -. DR MGI; MGI:1338889; Uhrf1. DR VEuPathDB; HostDB:ENSMUSG00000001228; -. DR eggNOG; ENOG502QRDQ; Eukaryota. DR GeneTree; ENSGT00390000008296; -. DR HOGENOM; CLU_022357_0_0_1; -. DR InParanoid; Q8VDF2; -. DR OMA; QIVMVNY; -. DR OrthoDB; 5481936at2759; -. DR PhylomeDB; Q8VDF2; -. DR TreeFam; TF106434; -. DR UniPathway; UPA00143; -. DR BioGRID-ORCS; 18140; 35 hits in 121 CRISPR screens. DR ChiTaRS; Uhrf1; mouse. DR EvolutionaryTrace; Q8VDF2; -. DR PRO; PR:Q8VDF2; -. DR Proteomes; UP000000589; Chromosome 17. DR RNAct; Q8VDF2; Protein. DR Bgee; ENSMUSG00000001228; Expressed in metanephric ureteric bud and 221 other cell types or tissues. DR ExpressionAtlas; Q8VDF2; baseline and differential. DR GO; GO:0000785; C:chromatin; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0000791; C:euchromatin; ISS:UniProtKB. DR GO; GO:0000792; C:heterochromatin; IDA:UniProtKB. DR GO; GO:0016363; C:nuclear matrix; IDA:BHF-UCL. DR GO; GO:0005654; C:nucleoplasm; ISO:MGI. DR GO; GO:0005634; C:nucleus; IDA:MGI. DR GO; GO:0005657; C:replication fork; IDA:UniProtKB. DR GO; GO:0000987; F:cis-regulatory region sequence-specific DNA binding; ISO:MGI. DR GO; GO:0044729; F:hemi-methylated DNA-binding; IDA:UniProtKB. DR GO; GO:0042393; F:histone binding; IDA:BHF-UCL. DR GO; GO:0141055; F:histone H3 ubiquitin ligase activity; IDA:BHF-UCL. DR GO; GO:0042802; F:identical protein binding; IPI:BHF-UCL. DR GO; GO:0008327; F:methyl-CpG binding; ISO:MGI. DR GO; GO:0035064; F:methylated histone binding; IDA:UniProtKB. DR GO; GO:0003676; F:nucleic acid binding; ISO:MGI. DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:BHF-UCL. DR GO; GO:0004842; F:ubiquitin-protein transferase activity; ISO:MGI. DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB. DR GO; GO:0006281; P:DNA repair; IEA:UniProtKB-KW. DR GO; GO:0031507; P:heterochromatin formation; ISS:UniProtKB. DR GO; GO:0090307; P:mitotic spindle assembly; IEA:Ensembl. DR GO; GO:0044027; P:negative regulation of gene expression via CpG island methylation; IMP:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0051247; P:positive regulation of protein metabolic process; ISO:MGI. DR GO; GO:0051865; P:protein autoubiquitination; ISO:MGI. DR GO; GO:0050678; P:regulation of epithelial cell proliferation; ISO:MGI. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; ISS:UniProtKB. DR CDD; cd15525; PHD_UHRF1_2; 1. DR CDD; cd17122; Ubl_UHRF1; 1. DR Gene3D; 2.30.30.1150; -; 1. DR Gene3D; 2.30.30.140; -; 1. DR Gene3D; 2.30.280.10; SRA-YDG; 1. DR Gene3D; 3.30.40.10; Zinc/RING finger domain, C3HC4 (zinc finger); 1. DR InterPro; IPR015947; PUA-like_sf. DR InterPro; IPR036987; SRA-YDG_sf. DR InterPro; IPR003105; SRA_YDG. DR InterPro; IPR021991; TTD_dom. DR InterPro; IPR000626; Ubiquitin-like_dom. DR InterPro; IPR029071; Ubiquitin-like_domsf. DR InterPro; IPR047406; Ubl_UHRF1. DR InterPro; IPR045134; UHRF1/2-like. DR InterPro; IPR011011; Znf_FYVE_PHD. DR InterPro; IPR001965; Znf_PHD. DR InterPro; IPR019787; Znf_PHD-finger. DR InterPro; IPR001841; Znf_RING. DR InterPro; IPR013083; Znf_RING/FYVE/PHD. DR InterPro; IPR017907; Znf_RING_CS. DR PANTHER; PTHR14140; E3 UBIQUITIN-PROTEIN LIGASE UHRF-RELATED; 1. DR PANTHER; PTHR14140:SF2; E3 UBIQUITIN-PROTEIN LIGASE UHRF1; 1. DR Pfam; PF00628; PHD; 1. DR Pfam; PF02182; SAD_SRA; 1. DR Pfam; PF12148; TTD; 1. DR Pfam; PF00240; ubiquitin; 1. DR SMART; SM00249; PHD; 1. DR SMART; SM00184; RING; 2. DR SMART; SM00466; SRA; 1. DR SMART; SM00213; UBQ; 1. DR SUPFAM; SSF57903; FYVE/PHD zinc finger; 1. DR SUPFAM; SSF88697; PUA domain-like; 1. DR SUPFAM; SSF57850; RING/U-box; 1. DR SUPFAM; SSF54236; Ubiquitin-like; 1. DR PROSITE; PS50053; UBIQUITIN_2; 1. DR PROSITE; PS51015; YDG; 1. DR PROSITE; PS01359; ZF_PHD_1; 1. DR PROSITE; PS50016; ZF_PHD_2; 1. DR PROSITE; PS00518; ZF_RING_1; 1. DR PROSITE; PS50089; ZF_RING_2; 2. DR Genevisible; Q8VDF2; MM. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Cell cycle; KW Chromatin regulator; DNA damage; DNA repair; DNA-binding; Isopeptide bond; KW Metal-binding; Nucleus; Phosphoprotein; Reference proteome; Repeat; KW Repressor; Transcription; Transcription regulation; Transferase; KW Ubl conjugation; Ubl conjugation pathway; Zinc; Zinc-finger. FT CHAIN 1..782 FT /note="E3 ubiquitin-protein ligase UHRF1" FT /id="PRO_0000056145" FT DOMAIN 1..78 FT /note="Ubiquitin-like" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00214" FT DOMAIN 424..586 FT /note="YDG" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00358" FT ZN_FING 304..371 FT /note="PHD-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00146" FT ZN_FING 713..752 FT /note="RING-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175" FT REGION 83..119 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 129..205 FT /note="Tudor-like 1" FT REGION 212..280 FT /note="Tudor-like 2" FT REGION 293..306 FT /note="Linker" FT /evidence="ECO:0000250" FT REGION 338..342 FT /note="Histone H3R2me0 binding" FT /evidence="ECO:0000250" FT REGION 358..360 FT /note="Histone H3R2me0 binding" FT /evidence="ECO:0000250" FT REGION 450..451 FT /note="Required to promote base flipping" FT REGION 471..474 FT /note="Required for formation of a 5-methylcytosine-binding FT pocket" FT REGION 483..486 FT /note="Required for formation of a 5-methylcytosine-binding FT pocket" FT REGION 623..666 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 105..119 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 635..666 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 468..469 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_part="5-methylcytosine group" FT /ligand_part_id="ChEBI:CHEBI:65274" FT /evidence="ECO:0000250" FT BINDING 474 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_part="5-methylcytosine group" FT /ligand_part_id="ChEBI:CHEBI:65274" FT /evidence="ECO:0000250" FT SITE 321 FT /note="Histone H3K4me0 binding" FT /evidence="ECO:0000250" FT SITE 332 FT /note="Histone H3R2me0 binding" FT /evidence="ECO:0000250" FT SITE 335 FT /note="Histone H3R2me0 binding" FT /evidence="ECO:0000250" FT SITE 484 FT /note="Required to confer preferential recognition of FT cytosine over thymine" FT /evidence="ECO:0000250" FT SITE 494 FT /note="Required to discriminate between hemimethylated DNA FT versus symmetrically methylated DNA" FT SITE 496 FT /note="Required for affinity and specificity for 5-mCpG FT sequence" FT MOD_RES 76 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q96T88" FT MOD_RES 91 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q96T88" FT MOD_RES 93 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q7TPK1" FT MOD_RES 95 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q7TPK1" FT MOD_RES 161 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 303 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000250|UniProtKB:Q96T88" FT MOD_RES 373 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q96T88" FT MOD_RES 404 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q96T88" FT MOD_RES 519 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 550 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:Q96T88" FT MOD_RES 639 FT /note="Phosphoserine; by CDK1" FT /evidence="ECO:0000250|UniProtKB:Q96T88" FT MOD_RES 649 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q96T88" FT MOD_RES 656 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19144319" FT MOD_RES 759 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q7TPK1" FT CROSSLNK 390 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0000250|UniProtKB:Q96T88" FT CROSSLNK 550 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2); alternate" FT /evidence="ECO:0000250|UniProtKB:Q96T88" FT CROSSLNK 664 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0000250|UniProtKB:Q96T88" FT VAR_SEQ 293..301 FT /note="PPPALRNTG -> R (in isoform 2)" FT /evidence="ECO:0000303|PubMed:16141072" FT /id="VSP_044395" FT MUTAGEN 148 FT /note="F->A: Abolishes binding to histone H3K9me3 and FT ability to repress transcription of target genes." FT /evidence="ECO:0000269|PubMed:21489993" FT MUTAGEN 730 FT /note="H->A: Abolishes enzymatic activity." FT /evidence="ECO:0000269|PubMed:14993289" FT CONFLICT 104 FT /note="S -> P (in Ref. 3; BAE30624)" FT /evidence="ECO:0000305" FT CONFLICT 118 FT /note="D -> G (in Ref. 3; FT BAE31708/BAE31605/BAE30730/BAE29605)" FT /evidence="ECO:0000305" FT CONFLICT 214 FT /note="E -> K (in Ref. 6; BAB79496)" FT /evidence="ECO:0000305" FT CONFLICT 449 FT /note="P -> L (in Ref. 6; BAB79496)" FT /evidence="ECO:0000305" FT CONFLICT 455..456 FT /note="HG -> PW (in Ref. 6; BAB79496)" FT /evidence="ECO:0000305" FT CONFLICT 471 FT /note="Y -> H (in Ref. 3; BAE27560)" FT /evidence="ECO:0000305" FT CONFLICT 637 FT /note="P -> A (in Ref. 3; BAE26398)" FT /evidence="ECO:0000305" FT CONFLICT 702 FT /note="I -> V (in Ref. 3; FT BAE31708/BAE31605/BAE30730/BAE29605)" FT /evidence="ECO:0000305" FT CONFLICT 753 FT /note="F -> Y (in Ref. 5; AAH22167)" FT /evidence="ECO:0000305" FT STRAND 135..140 FT /evidence="ECO:0007829|PDB:6VEE" FT STRAND 142..144 FT /evidence="ECO:0007829|PDB:6VEE" FT STRAND 147..156 FT /evidence="ECO:0007829|PDB:6VEE" FT STRAND 179..186 FT /evidence="ECO:0007829|PDB:6VEE" FT HELIX 188..190 FT /evidence="ECO:0007829|PDB:6VEE" FT STRAND 193..196 FT /evidence="ECO:0007829|PDB:6VEE" FT HELIX 197..199 FT /evidence="ECO:0007829|PDB:6VEE" FT STRAND 200..202 FT /evidence="ECO:0007829|PDB:6VEE" FT HELIX 210..212 FT /evidence="ECO:0007829|PDB:6VEE" FT STRAND 218..223 FT /evidence="ECO:0007829|PDB:6VEE" FT STRAND 233..245 FT /evidence="ECO:0007829|PDB:6VEE" FT STRAND 248..257 FT /evidence="ECO:0007829|PDB:6VEE" FT TURN 258..260 FT /evidence="ECO:0007829|PDB:6VEE" FT STRAND 261..267 FT /evidence="ECO:0007829|PDB:6VEE" FT TURN 271..273 FT /evidence="ECO:0007829|PDB:6VEE" FT STRAND 274..276 FT /evidence="ECO:0007829|PDB:6VEE" FT TURN 308..312 FT /evidence="ECO:0007829|PDB:6VFO" FT HELIX 319..321 FT /evidence="ECO:0007829|PDB:6VFO" FT TURN 324..327 FT /evidence="ECO:0007829|PDB:6VFO" FT HELIX 332..334 FT /evidence="ECO:0007829|PDB:6VFO" FT STRAND 335..338 FT /evidence="ECO:0007829|PDB:6VFO" FT TURN 339..342 FT /evidence="ECO:0007829|PDB:6VFO" FT STRAND 343..346 FT /evidence="ECO:0007829|PDB:6VFO" FT HELIX 347..349 FT /evidence="ECO:0007829|PDB:6VFO" FT STRAND 350..352 FT /evidence="ECO:0007829|PDB:6VFO" FT HELIX 366..368 FT /evidence="ECO:0007829|PDB:6VFO" FT TURN 405..408 FT /evidence="ECO:0007829|PDB:2ZKD" FT STRAND 434..437 FT /evidence="ECO:0007829|PDB:3FDE" FT HELIX 438..443 FT /evidence="ECO:0007829|PDB:3FDE" FT STRAND 453..457 FT /evidence="ECO:0007829|PDB:3FDE" FT TURN 458..460 FT /evidence="ECO:0007829|PDB:3FDE" FT STRAND 461..467 FT /evidence="ECO:0007829|PDB:3FDE" FT STRAND 475..477 FT /evidence="ECO:0007829|PDB:2ZO1" FT STRAND 478..484 FT /evidence="ECO:0007829|PDB:3FDE" FT TURN 492..494 FT /evidence="ECO:0007829|PDB:3FDE" FT HELIX 508..515 FT /evidence="ECO:0007829|PDB:3FDE" FT STRAND 517..519 FT /evidence="ECO:0007829|PDB:3FDE" FT HELIX 531..533 FT /evidence="ECO:0007829|PDB:3FDE" FT STRAND 537..543 FT /evidence="ECO:0007829|PDB:3FDE" FT TURN 546..548 FT /evidence="ECO:0007829|PDB:2ZO2" FT STRAND 550..552 FT /evidence="ECO:0007829|PDB:3FDE" FT STRAND 554..572 FT /evidence="ECO:0007829|PDB:3FDE" FT STRAND 576..586 FT /evidence="ECO:0007829|PDB:3FDE" FT HELIX 596..605 FT /evidence="ECO:0007829|PDB:3FDE" FT HELIX 615..622 FT /evidence="ECO:0007829|PDB:3FDE" SQ SEQUENCE 782 AA; 88304 MW; DC5EEDFCDF69619B CRC64; MWIQVRTMDG KETHTVNSLS RLTKVQELRK KIEEVFHVEP QLQRLFYRGK QMEDGHTLFD YDVRLNDTIQ LLVRQSLALP LSTKERDSEL SDSDSGYGVG HSESDKSSTH GEGAAEADDK TVWEDTDLGL YKVNEYVDVR DNIFGAWFEA QVVQVQKRAL SEDEPCSSSA VKTSEDDIMY HVKYDDYPEH GVDIVKAKNV RARARTVIPW ENLEVGQVVM ANYNVDYPRK RGFWYDVEIC RKRQTRTARE LYGNIRLLND SQLNNCRIMF VDEVLMIELP KERRPLIASP SQPPPALRNT GKSGPSCRFC KDDENKPCRK CACHVCGGRE APEKQLLCDE CDMAFHLYCL KPPLTSVPPE PEWYCPSCRT DSSEVVQAGE KLKESKKKAK MASATSSSRR DWGKGMACVG RTTECTIVPA NHFGPIPGVP VGTMWRFRVQ VSESGVHRPH VAGIHGRSND GAYSLVLAGG YEDDVDNGNY FTYTGSGGRD LSGNKRTAGQ SSDQKLTNNN RALALNCHSP INEKGAEAED WRQGKPVRVV RNMKGGKHSK YAPAEGNRYD GIYKVVKYWP ERGKSGFLVW RYLLRRDDTE PEPWTREGKD RTRQLGLTMQ YPEGYLEALA NKEKSRKRPA KALEQGPSSS KTGKSKQKST GPTLSSPRAS KKSKLEPYTL SEQQANLIKE DKGNAKLWDD VLTSLQDGPY QIFLSKVKEA FQCICCQELV FRPVTTVCQH NVCKDCLDRS FRAQVFSCPA CRFELDHSSP TRVNQPLQTI LNQLFPGYGS GR //