ID HERC2_HUMAN Reviewed; 4834 AA.
AC O95714; Q86SV7; Q86SV8; Q86SV9; Q86YY3; Q86YY4; Q86YY5; Q86YY6; Q86YY7;
AC Q86YY8; Q86YY9; Q86YZ0; Q86YZ1;
DT 04-APR-2006, integrated into UniProtKB/Swiss-Prot.
DT 05-OCT-2010, sequence version 2.
DT 27-MAR-2024, entry version 198.
DE RecName: Full=E3 ubiquitin-protein ligase HERC2;
DE EC=2.3.2.26 {ECO:0000269|PubMed:20304803};
DE AltName: Full=HECT domain and RCC1-like domain-containing protein 2;
DE AltName: Full=HECT-type E3 ubiquitin transferase HERC2;
GN Name=HERC2 {ECO:0000312|EMBL:AAD08657.1};
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] {ECO:0000312|EMBL:AAD08657.1}
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9949213; DOI=10.1093/hmg/8.3.533;
RA Ji Y., Walkowicz M.J., Buiting K., Johnson D.K., Tarvin R.E., Rinchik E.M.,
RA Horsthemke B., Stubbs L., Nicholls R.D.;
RT "The ancestral gene for transcribed, low-copy repeats in the Prader-
RT Willi/Angelman region encodes a large protein implicated in protein
RT trafficking, which is deficient in mice with neuromuscular and spermiogenic
RT abnormalities.";
RL Hum. Mol. Genet. 8:533-542(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16572171; DOI=10.1038/nature04601;
RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J.,
RA Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E.,
RA Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B.,
RA Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R.,
RA O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B.,
RA Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S.,
RA Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.;
RT "Analysis of the DNA sequence and duplication history of human chromosome
RT 15.";
RL Nature 440:671-675(2006).
RN [3] {ECO:0000305, ECO:0000312|EMBL:AAO27483.1}
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 2818-2895; 2909-2957; 2963-3290;
RP 3317-3363; 3389-3430; 3458-3495; 3512-3527; 3533-3633; 3635-3821;
RP 3826-4084; 4097-4505 AND 4529-4834, AND GENE STRUCTURE.
RX PubMed=10720573; DOI=10.1101/gr.10.3.319;
RA Ji Y., Rebert N.A., Joslin J.M., Higgins M.J., Schultz R.A., Nicholls R.D.;
RT "Structure of the highly conserved HERC2 gene and of multiple partially
RT duplicated paralogs in human.";
RL Genome Res. 10:319-329(2000).
RN [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2454 AND SER-2928, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT networks.";
RL Cell 127:635-648(2006).
RN [5]
RP INVOLVEMENT IN SHEP1.
RX PubMed=18252221; DOI=10.1016/j.ajhg.2007.10.003;
RA Kayser M., Liu F., Janssens A.C.J.W., Rivadeneira F., Lao O., van Duijn K.,
RA Vermeulen M., Arp P., Jhamai M.M., van Ijcken W.F.J., den Dunnen J.T.,
RA Heath S., Zelenika D., Despriet D.D.G., Klaver C.C.W., Vingerling J.R.,
RA de Jong P.T.V.M., Hofman A., Aulchenko Y.S., Uitterlinden A.G.,
RA Oostra B.A., van Duijn C.M.;
RT "Three genome-wide association studies and a linkage analysis identify
RT HERC2 as a human iris color gene.";
RL Am. J. Hum. Genet. 82:411-423(2008).
RN [6]
RP INVOLVEMENT IN SHEP1.
RX PubMed=18252222; DOI=10.1016/j.ajhg.2007.11.005;
RA Sturm R.A., Duffy D.L., Zhao Z.Z., Leite F.P.M., Stark M.S., Hayward N.K.,
RA Martin N.G., Montgomery G.W.;
RT "A single SNP in an evolutionary conserved region within intron 86 of the
RT HERC2 gene determines human blue-brown eye color.";
RL Am. J. Hum. Genet. 82:424-431(2008).
RN [7]
RP INVOLVEMENT IN SHEP1, AND REGULATION OF OCA2.
RX PubMed=18172690; DOI=10.1007/s00439-007-0460-x;
RA Eiberg H., Troelsen J., Nielsen M., Mikkelsen A., Mengel-From J.,
RA Kjaer K.W., Hansen L.;
RT "Blue eye color in humans may be caused by a perfectly associated founder
RT mutation in a regulatory element located within the HERC2 gene inhibiting
RT OCA2 expression.";
RL Hum. Genet. 123:177-187(2008).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2928; SER-4810; SER-4811 AND
RP SER-4814, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2454, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [11]
RP MISCELLANEOUS.
RX PubMed=20457063; DOI=10.1016/j.fsigen.2009.12.004;
RA Mengel-From J., Borsting C., Sanchez J.J., Eiberg H., Morling N.;
RT "Human eye colour and HERC2, OCA2 and MATP.";
RL Forensic Sci. Int. Genet. 4:323-328(2010).
RN [12]
RP FUNCTION, INTERACTION WITH RNF8, PHOSPHORYLATION AT THR-4827, MUTAGENESIS
RP OF THR-4827, AND SUBCELLULAR LOCATION.
RX PubMed=20023648; DOI=10.1038/ncb2008;
RA Bekker-Jensen S., Rendtlew Danielsen J., Fugger K., Gromova I.,
RA Nerstedt A., Lukas C., Bartek J., Lukas J., Mailand N.;
RT "HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on
RT damaged chromosomes.";
RL Nat. Cell Biol. 12:80-86(2010).
RN [13]
RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH XPA, AND SUBCELLULAR
RP LOCATION.
RX PubMed=20304803; DOI=10.1073/pnas.0915085107;
RA Kang T.H., Lindsey-Boltz L.A., Reardon J.T., Sancar A.;
RT "Circadian control of XPA and excision repair of cisplatin-DNA damage by
RT cryptochrome and HERC2 ubiquitin ligase.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:4890-4895(2010).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2454 AND SER-2928, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-647; THR-1944 AND SER-2928,
RP AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [17]
RP SUMOYLATION, FUNCTION, SUMO-BINDING, DOMAIN, INTERACTION WITH RNF8, AND
RP MUTAGENESIS OF CYS-2708 AND CYS-2711.
RX PubMed=22508508; DOI=10.1083/jcb.201106152;
RA Danielsen J.R., Povlsen L.K., Villumsen B.H., Streicher W., Nilsson J.,
RA Wikstrom M., Bekker-Jensen S., Mailand N.;
RT "DNA damage-inducible SUMOylation of HERC2 promotes RNF8 binding via a
RT novel SUMO-binding Zinc finger.";
RL J. Cell Biol. 197:179-187(2012).
RN [18]
RP INTERACTION WITH CCP110; CEP97 AND NEURL4, AND SUBCELLULAR LOCATION.
RX PubMed=22261722; DOI=10.1074/mcp.m111.014233;
RA Al-Hakim A.K., Bashkurov M., Gingras A.C., Durocher D., Pelletier L.;
RT "Interaction proteomics identify NEURL4 and the HECT E3 ligase HERC2 as
RT novel modulators of centrosome architecture.";
RL Mol. Cell. Proteomics 11:M111.014233.01-M111.014233.14(2012).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-272; SER-2454 AND SER-2928,
RP AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [20]
RP FUNCTION.
RX PubMed=24778179; DOI=10.1074/jbc.m113.541490;
RA Moroishi T., Yamauchi T., Nishiyama M., Nakayama K.I.;
RT "HERC2 targets the iron regulator FBXL5 for degradation and modulates iron
RT metabolism.";
RL J. Biol. Chem. 289:16430-16441(2014).
RN [21]
RP FUNCTION.
RX PubMed=26692333; DOI=10.1038/nm.4013;
RA Osorio F.G., Soria-Valles C., Santiago-Fernandez O., Bernal T.,
RA Mittelbrunn M., Colado E., Rodriguez F., Bonzon-Kulichenko E., Vazquez J.,
RA Porta-de-la-Riva M., Ceron J., Fueyo A., Li J., Green A.R., Freije J.M.,
RA Lopez-Otin C.;
RT "Loss of the proteostasis factor AIRAPL causes myeloid transformation by
RT deregulating IGF-1 signaling.";
RL Nat. Med. 22:91-96(2016).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 417-790, AND RCC1 REPEATS.
RA Tempel W., Khan M.B., Dong A., Hu J., Li Y., Bountra C., Arrowsmith C.H.,
RA Edwards A.M., Tong Y.;
RT "Structure of the first RCC1-like domain of HERC2.";
RL Submitted (JUN-2013) to the PDB data bank.
RN [23]
RP VARIANT MRT38 LEU-594, AND CHARACTERIZATION OF VARIANT MRT38 LEU-594.
RX PubMed=23065719; DOI=10.1002/humu.22237;
RA Puffenberger E.G., Jinks R.N., Wang H., Xin B., Fiorentini C.,
RA Sherman E.A., Degrazio D., Shaw C., Sougnez C., Cibulskis K., Gabriel S.,
RA Kelley R.I., Morton D.H., Strauss K.A.;
RT "A homozygous missense mutation in HERC2 associated with global
RT developmental delay and autism spectrum disorder.";
RL Hum. Mutat. 33:1639-1646(2012).
CC -!- FUNCTION: E3 ubiquitin-protein ligase that regulates ubiquitin-
CC dependent retention of repair proteins on damaged chromosomes.
CC Recruited to sites of DNA damage in response to ionizing radiation (IR)
CC and facilitates the assembly of UBE2N and RNF8 promoting DNA damage-
CC induced formation of 'Lys-63'-linked ubiquitin chains. Acts as a
CC mediator of binding specificity between UBE2N and RNF8. Involved in the
CC maintenance of RNF168 levels. E3 ubiquitin-protein ligase that promotes
CC the ubiquitination and proteasomal degradation of XPA which influences
CC the circadian oscillation of DNA excision repair activity. By
CC controlling the steady-state expression of the IGF1R receptor,
CC indirectly regulates the insulin-like growth factor receptor signaling
CC pathway (PubMed:26692333). Modulates also iron metabolism by regulating
CC the basal turnover of FBXL5 (PubMed:24778179).
CC {ECO:0000269|PubMed:20023648, ECO:0000269|PubMed:20304803,
CC ECO:0000269|PubMed:22508508, ECO:0000269|PubMed:24778179,
CC ECO:0000269|PubMed:26692333}.
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=2.3.2.26; Evidence={ECO:0000269|PubMed:20304803};
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Interacts (when phosphorylated at Thr-4827 and sumoylated)
CC with RNF8 (via FHA domain); this interaction increases after ionizing
CC radiation (IR) treatment. Interacts with XPA. Interacts with NEURL4.
CC Via its interaction with NEURL4, may indirectly interact with CCP110
CC and CEP97. {ECO:0000269|PubMed:20023648, ECO:0000269|PubMed:20304803,
CC ECO:0000269|PubMed:22261722, ECO:0000269|PubMed:22508508}.
CC -!- INTERACTION:
CC O95714; Q9BXG8: SPZ1; NbExp=2; IntAct=EBI-1058922, EBI-8483734;
CC O95714; Q05086-2: UBE3A; NbExp=5; IntAct=EBI-1058922, EBI-10175863;
CC O95714; P23025: XPA; NbExp=4; IntAct=EBI-1058922, EBI-295222;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cytoplasm, cytoskeleton, microtubule
CC organizing center, centrosome, centriole. Nucleus. Note=Recruited to
CC sites of DNA damage in response to ionizing radiation (IR) via its
CC interaction with RNF8. May loose association with centrosomes during
CC mitosis.
CC -!- DOMAIN: The ZZ-type zinc finger mediates binding to SUMO1, and at low
CC level SUMO2. {ECO:0000269|PubMed:22508508}.
CC -!- DOMAIN: The RCC1 repeats are grouped into three seven-bladed beta-
CC propeller regions. {ECO:0000269|PubMed:22508508}.
CC -!- PTM: Phosphorylation at Thr-4827 is required for interaction with RNF8.
CC {ECO:0000269|PubMed:20023648}.
CC -!- PTM: Sumoylated with SUMO1 by PIAS4 in response to double-strand breaks
CC (DSBs), promoting the interaction with RNF8.
CC {ECO:0000269|PubMed:22508508}.
CC -!- POLYMORPHISM: Genetic variants in HERC2 define the skin/hair/eye
CC pigmentation variation locus 1 (SHEP1) [MIM:227220]; also known as
CC skin/hair/eye pigmentation type 1, blue/nonblue eyes or skin/hair/eye
CC pigmentation type 1, blue/brown eyes or skin/hair/eye pigmentation type
CC 1, blond/brown hair or eye color, brown/blue or eye color, blue/nonblue
CC or eye color type 3 (EYCL3) or brown eye color type 2 (BEY2) or hair
CC color type 3 (HCL3). Hair, eye and skin pigmentation are among the most
CC visible examples of human phenotypic variation, with a broad normal
CC range that is subject to substantial geographic stratification. In the
CC case of skin, individuals tend to have lighter pigmentation with
CC increasing distance from the equator. By contrast, the majority of
CC variation in human eye and hair color is found among individuals of
CC European ancestry, with most other human populations fixed for brown
CC eyes and black hair.
CC -!- DISEASE: Intellectual developmental disorder, autosomal recessive 38
CC (MRT38) [MIM:615516]: A disorder characterized by significantly below
CC average general intellectual functioning associated with impairments in
CC adaptive behavior and manifested during the developmental period. MRT38
CC is characterized by global developmental delay affecting motor, speech,
CC adaptive, and social development. Patients manifest autistic features,
CC aggression, self-injury, impulsivity, and distractibility.
CC {ECO:0000269|PubMed:23065719}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: A regulatory element within an intron of the HERC2 gene
CC inhibits OCA2 promoter. There are several single nucleotide
CC polymorphisms within the OCA2 gene and within the HERC2 gene that have
CC a statistical association with human eye color.
CC -!- WEB RESOURCE: Name=Hect domain and RLD 2 (HERC2); Note=Leiden Open
CC Variation Database (LOVD);
CC URL="https://databases.lovd.nl/shared/genes/HERC2";
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DR EMBL; AF071172; AAD08657.1; -; mRNA.
DR EMBL; AC091304; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC126332; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC135329; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AF224243; AAO27473.1; -; Genomic_DNA.
DR EMBL; AF224242; AAO27473.1; JOINED; Genomic_DNA.
DR EMBL; AF224245; AAO27474.1; -; Genomic_DNA.
DR EMBL; AF224244; AAO27474.1; JOINED; Genomic_DNA.
DR EMBL; AF224249; AAO27475.1; -; Genomic_DNA.
DR EMBL; AF224246; AAO27475.1; JOINED; Genomic_DNA.
DR EMBL; AF224247; AAO27475.1; JOINED; Genomic_DNA.
DR EMBL; AF224248; AAO27475.1; JOINED; Genomic_DNA.
DR EMBL; AF224251; AAO27476.1; -; Genomic_DNA.
DR EMBL; AF224250; AAO27476.1; JOINED; Genomic_DNA.
DR EMBL; AF224255; AAO27479.1; -; Genomic_DNA.
DR EMBL; AF224254; AAO27479.1; JOINED; Genomic_DNA.
DR EMBL; AF224252; AAO27477.1; -; Genomic_DNA.
DR EMBL; AF224253; AAO27478.1; -; Genomic_DNA.
DR EMBL; AF224257; AAO27480.1; -; Genomic_DNA.
DR EMBL; AF224256; AAO27480.1; JOINED; Genomic_DNA.
DR EMBL; AF225401; AAO27481.1; -; Genomic_DNA.
DR EMBL; AF225400; AAO27481.1; JOINED; Genomic_DNA.
DR EMBL; AF225404; AAO27482.1; -; Genomic_DNA.
DR EMBL; AF225402; AAO27482.1; JOINED; Genomic_DNA.
DR EMBL; AF225403; AAO27482.1; JOINED; Genomic_DNA.
DR EMBL; AF225407; AAO27483.1; -; Genomic_DNA.
DR EMBL; AF225405; AAO27483.1; JOINED; Genomic_DNA.
DR EMBL; AF225406; AAO27483.1; JOINED; Genomic_DNA.
DR EMBL; AF225409; AAO27484.1; -; Genomic_DNA.
DR EMBL; AF225408; AAO27484.1; JOINED; Genomic_DNA.
DR CCDS; CCDS10021.1; -.
DR RefSeq; NP_004658.3; NM_004667.5.
DR PDB; 2KEO; NMR; -; A=1203-1296.
DR PDB; 3KCI; X-ray; 1.80 A; A=3951-4321.
DR PDB; 4L1M; X-ray; 2.60 A; A/B/C=417-790.
DR PDB; 6WW3; X-ray; 2.10 A; A/B=2702-2755.
DR PDB; 6WW4; X-ray; 2.25 A; A/B=2702-2751.
DR PDB; 7Q40; X-ray; 2.35 A; A/C/E=2938-3342.
DR PDB; 7Q41; X-ray; 3.01 A; A/C/E=2938-3342.
DR PDB; 7Q42; X-ray; 1.95 A; A/C/E=2938-3342.
DR PDB; 7Q43; X-ray; 2.40 A; A/C/E=2941-3342.
DR PDB; 7Q44; X-ray; 2.20 A; A/C/E=2941-3342.
DR PDB; 7Q45; X-ray; 2.10 A; A/C/E=2938-3342.
DR PDB; 7Q46; X-ray; 2.46 A; A/C/E=2941-3342.
DR PDB; 7RGW; X-ray; 1.99 A; A=2759-2914.
DR PDBsum; 2KEO; -.
DR PDBsum; 3KCI; -.
DR PDBsum; 4L1M; -.
DR PDBsum; 6WW3; -.
DR PDBsum; 6WW4; -.
DR PDBsum; 7Q40; -.
DR PDBsum; 7Q41; -.
DR PDBsum; 7Q42; -.
DR PDBsum; 7Q43; -.
DR PDBsum; 7Q44; -.
DR PDBsum; 7Q45; -.
DR PDBsum; 7Q46; -.
DR PDBsum; 7RGW; -.
DR SMR; O95714; -.
DR BioGRID; 114438; 464.
DR CORUM; O95714; -.
DR DIP; DIP-37632N; -.
DR IntAct; O95714; 138.
DR MINT; O95714; -.
DR STRING; 9606.ENSP00000261609; -.
DR GlyConnect; 1191; 2 N-Linked glycans (2 sites).
DR GlyCosmos; O95714; 4 sites, 4 glycans.
DR GlyGen; O95714; 6 sites, 3 N-linked glycans (2 sites), 1 O-linked glycan (4 sites).
DR iPTMnet; O95714; -.
DR PhosphoSitePlus; O95714; -.
DR SwissPalm; O95714; -.
DR BioMuta; HERC2; -.
DR EPD; O95714; -.
DR jPOST; O95714; -.
DR MassIVE; O95714; -.
DR MaxQB; O95714; -.
DR PaxDb; 9606-ENSP00000261609; -.
DR PeptideAtlas; O95714; -.
DR ProteomicsDB; 51008; -.
DR Pumba; O95714; -.
DR Antibodypedia; 22335; 70 antibodies from 11 providers.
DR DNASU; 8924; -.
DR Ensembl; ENST00000261609.13; ENSP00000261609.8; ENSG00000128731.18.
DR GeneID; 8924; -.
DR KEGG; hsa:8924; -.
DR MANE-Select; ENST00000261609.13; ENSP00000261609.8; NM_004667.6; NP_004658.3.
DR UCSC; uc001zbj.5; human.
DR AGR; HGNC:4868; -.
DR CTD; 8924; -.
DR DisGeNET; 8924; -.
DR GeneCards; HERC2; -.
DR GeneReviews; HERC2; -.
DR HGNC; HGNC:4868; HERC2.
DR HPA; ENSG00000128731; Low tissue specificity.
DR MalaCards; HERC2; -.
DR MIM; 227220; phenotype.
DR MIM; 605837; gene.
DR MIM; 615516; phenotype.
DR neXtProt; NX_O95714; -.
DR OpenTargets; ENSG00000128731; -.
DR Orphanet; 329195; Developmental delay with autism spectrum disorder and gait instability.
DR PharmGKB; PA29243; -.
DR VEuPathDB; HostDB:ENSG00000128731; -.
DR eggNOG; KOG1426; Eukaryota.
DR GeneTree; ENSGT00940000154975; -.
DR HOGENOM; CLU_000101_0_0_1; -.
DR InParanoid; O95714; -.
DR OMA; HTNGVLY; -.
DR OrthoDB; 5491782at2759; -.
DR PhylomeDB; O95714; -.
DR TreeFam; TF320636; -.
DR PathwayCommons; O95714; -.
DR Reactome; R-HSA-3108214; SUMOylation of DNA damage response and repair proteins.
DR Reactome; R-HSA-5693565; Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks.
DR Reactome; R-HSA-5693571; Nonhomologous End-Joining (NHEJ).
DR Reactome; R-HSA-5693607; Processing of DNA double-strand break ends.
DR Reactome; R-HSA-69473; G2/M DNA damage checkpoint.
DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR SignaLink; O95714; -.
DR SIGNOR; O95714; -.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 8924; 45 hits in 1203 CRISPR screens.
DR ChiTaRS; HERC2; human.
DR EvolutionaryTrace; O95714; -.
DR GeneWiki; HERC2; -.
DR GenomeRNAi; 8924; -.
DR Pharos; O95714; Tbio.
DR PRO; PR:O95714; -.
DR Proteomes; UP000005640; Chromosome 15.
DR RNAct; O95714; Protein.
DR Bgee; ENSG00000128731; Expressed in sural nerve and 96 other cell types or tissues.
DR ExpressionAtlas; O95714; baseline and differential.
DR Genevisible; O95714; HS.
DR GO; GO:0005814; C:centriole; IEA:UniProtKB-SubCell.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0005085; F:guanyl-nucleotide exchange factor activity; NAS:UniProtKB.
DR GO; GO:0032183; F:SUMO binding; IDA:UniProtKB.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:UniProtKB.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0006974; P:DNA damage response; IDA:UniProtKB.
DR GO; GO:0006281; P:DNA repair; IEA:UniProtKB-KW.
DR GO; GO:0006886; P:intracellular protein transport; NAS:UniProtKB.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IEA:Ensembl.
DR GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB.
DR GO; GO:0007283; P:spermatogenesis; IEA:Ensembl.
DR CDD; cd08664; APC10-HERC2; 1.
DR CDD; cd00078; HECTc; 1.
DR CDD; cd14402; UBA_HERC2; 1.
DR CDD; cd02344; ZZ_HERC2; 1.
DR Gene3D; 2.30.30.30; -; 1.
DR Gene3D; 3.30.60.90; -; 1.
DR Gene3D; 3.10.120.10; Cytochrome b5-like heme/steroid binding domain; 1.
DR Gene3D; 2.60.120.260; Galactose-binding domain-like; 1.
DR Gene3D; 3.30.2160.10; Hect, E3 ligase catalytic domain; 1.
DR Gene3D; 3.30.2410.10; Hect, E3 ligase catalytic domain; 1.
DR Gene3D; 3.90.1750.10; Hect, E3 ligase catalytic domains; 1.
DR Gene3D; 2.130.10.30; Regulator of chromosome condensation 1/beta-lactamase-inhibitor protein II; 3.
DR Gene3D; 2.30.30.40; SH3 Domains; 1.
DR InterPro; IPR004939; APC_su10/DOC_dom.
DR InterPro; IPR006624; Beta-propeller_rpt_TECPR.
DR InterPro; IPR021097; CPH_domain.
DR InterPro; IPR001199; Cyt_B5-like_heme/steroid-bd.
DR InterPro; IPR036400; Cyt_B5-like_heme/steroid_sf.
DR InterPro; IPR008979; Galactose-bd-like_sf.
DR InterPro; IPR000569; HECT_dom.
DR InterPro; IPR035983; Hect_E3_ubiquitin_ligase.
DR InterPro; IPR037976; HERC2_APC10.
DR InterPro; IPR010606; Mib_Herc2.
DR InterPro; IPR037252; Mib_Herc2_sf.
DR InterPro; IPR009091; RCC1/BLIP-II.
DR InterPro; IPR000408; Reg_chr_condens.
DR InterPro; IPR014722; Rib_uL2_dom2.
DR InterPro; IPR000433; Znf_ZZ.
DR InterPro; IPR043145; Znf_ZZ_sf.
DR InterPro; IPR041987; ZZ_HERC2.
DR PANTHER; PTHR22870; REGULATOR OF CHROMOSOME CONDENSATION; 1.
DR PANTHER; PTHR22870:SF437; X-LINKED RETINITIS PIGMENTOSA GTPASE REGULATOR-RELATED; 1.
DR Pfam; PF03256; ANAPC10; 1.
DR Pfam; PF11515; Cul7; 1.
DR Pfam; PF00173; Cyt-b5; 1.
DR Pfam; PF00632; HECT; 1.
DR Pfam; PF06701; MIB_HERC2; 1.
DR Pfam; PF00415; RCC1; 17.
DR Pfam; PF00569; ZZ; 1.
DR PRINTS; PR00633; RCCNDNSATION.
DR SMART; SM01337; APC10; 1.
DR SMART; SM01117; Cyt-b5; 1.
DR SMART; SM00119; HECTc; 1.
DR SMART; SM00706; TECPR; 5.
DR SMART; SM00291; ZnF_ZZ; 1.
DR SUPFAM; SSF55856; Cytochrome b5-like heme/steroid binding domain; 1.
DR SUPFAM; SSF49785; Galactose-binding domain-like; 1.
DR SUPFAM; SSF56204; Hect, E3 ligase catalytic domain; 1.
DR SUPFAM; SSF159034; Mib/herc2 domain-like; 1.
DR SUPFAM; SSF50985; RCC1/BLIP-II; 3.
DR SUPFAM; SSF63748; Tudor/PWWP/MBT; 1.
DR PROSITE; PS50255; CYTOCHROME_B5_2; 1.
DR PROSITE; PS51284; DOC; 1.
DR PROSITE; PS50237; HECT; 1.
DR PROSITE; PS51416; MIB_HERC2; 1.
DR PROSITE; PS00626; RCC1_2; 1.
DR PROSITE; PS50012; RCC1_3; 18.
DR PROSITE; PS01357; ZF_ZZ_1; 1.
DR PROSITE; PS50135; ZF_ZZ_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Coiled coil; Cytoplasm; Cytoskeleton; Disease variant;
KW DNA damage; DNA repair; Intellectual disability; Metal-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Repeat; Transferase; Ubl conjugation;
KW Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN 1..4834
FT /note="E3 ubiquitin-protein ligase HERC2"
FT /id="PRO_0000229739"
FT REPEAT 415..461
FT /note="RCC1 1-1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00235,
FT ECO:0000269|Ref.22"
FT REPEAT 462..512
FT /note="RCC1 1-2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00235,
FT ECO:0000269|Ref.22"
FT REPEAT 513..568
FT /note="RCC1 1-3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00235,
FT ECO:0000269|Ref.22"
FT REPEAT 569..620
FT /note="RCC1 1-4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00235,
FT ECO:0000269|Ref.22"
FT REPEAT 623..674
FT /note="RCC1 1-5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00235,
FT ECO:0000269|Ref.22"
FT REPEAT 675..726
FT /note="RCC1 1-6"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00235,
FT ECO:0000269|Ref.22"
FT REPEAT 728..778
FT /note="RCC1 1-7"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00235,
FT ECO:0000269|Ref.22"
FT DOMAIN 1207..1283
FT /note="Cytochrome b5 heme-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00279"
FT DOMAIN 1859..1932
FT /note="MIB/HERC2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00749"
FT DOMAIN 2759..2936
FT /note="DOC"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00614"
FT REPEAT 2958..3009
FT /note="RCC1 2-1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00235,
FT ECO:0000269|Ref.22"
FT REPEAT 3010..3064
FT /note="RCC1 2-2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00235,
FT ECO:0000269|Ref.22"
FT REPEAT 3065..3116
FT /note="RCC1 2-3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00235,
FT ECO:0000269|Ref.22"
FT REPEAT 3118..3168
FT /note="RCC1 2-4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00235,
FT ECO:0000269|Ref.22"
FT REPEAT 3171..3222
FT /note="RCC1 2-5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00235,
FT ECO:0000269|Ref.22"
FT REPEAT 3224..3274
FT /note="RCC1 2-6"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00235,
FT ECO:0000269|Ref.22"
FT REPEAT 3275..3326
FT /note="RCC1 2-7"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00235,
FT ECO:0000269|Ref.22"
FT REPEAT 3951..4002
FT /note="RCC1 3-1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00235,
FT ECO:0000269|Ref.22"
FT REPEAT 4004..4056
FT /note="RCC1 3-2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00235,
FT ECO:0000269|Ref.22"
FT REPEAT 4058..4108
FT /note="RCC1 3-3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00235,
FT ECO:0000269|Ref.22"
FT REPEAT 4110..4162
FT /note="RCC1 3-4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00235,
FT ECO:0000269|Ref.22"
FT REPEAT 4164..4214
FT /note="RCC1 3-5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00235,
FT ECO:0000269|Ref.22"
FT REPEAT 4216..4266
FT /note="RCC1 3-6"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00235,
FT ECO:0000269|Ref.22"
FT REPEAT 4268..4318
FT /note="RCC1 3-7"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00235,
FT ECO:0000269|Ref.22"
FT DOMAIN 4457..4794
FT /note="HECT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT ZN_FING 2703..2755
FT /note="ZZ-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228"
FT REGION 50..88
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1555..1575
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1933..1958
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 3602..3629
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 4804..4834
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 948..980
FT /evidence="ECO:0000255"
FT COMPBIAS 57..88
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 4808..4822
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 4762
FT /note="Glycyl thioester intermediate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00104"
FT BINDING 2708
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228"
FT BINDING 2711
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228"
FT BINDING 2723
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228"
FT BINDING 2726
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228"
FT BINDING 2732
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228"
FT BINDING 2735
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228"
FT BINDING 2741
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228"
FT BINDING 2745
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00228"
FT MOD_RES 272
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 647
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21406692"
FT MOD_RES 1577
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q4U2R1"
FT MOD_RES 1942
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q4U2R1"
FT MOD_RES 1944
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21406692"
FT MOD_RES 2454
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17081983,
FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 2928
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17081983,
FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"
FT MOD_RES 4810
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 4811
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 4814
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 4827
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:20023648"
FT VARIANT 594
FT /note="P -> L (in MRT38; decreased protein abundance in
FT transfected cells; dbSNP:rs397518474)"
FT /evidence="ECO:0000269|PubMed:23065719"
FT /id="VAR_069282"
FT MUTAGEN 2708
FT /note="C->S: Abolishes binding to SUMO; when associated
FT with S-2711."
FT /evidence="ECO:0000269|PubMed:22508508"
FT MUTAGEN 2711
FT /note="C->S: Abolishes binding to SUMO; when associated
FT with S-2708."
FT /evidence="ECO:0000269|PubMed:22508508"
FT MUTAGEN 4827
FT /note="T->A: Prevents HERC2 C-terminal fragment binding to
FT endogenous RNF8."
FT /evidence="ECO:0000269|PubMed:20023648"
FT CONFLICT 1053
FT /note="L -> W (in Ref. 1; AAD08657)"
FT /evidence="ECO:0000305"
FT CONFLICT 1150
FT /note="G -> D (in Ref. 1; AAD08657)"
FT /evidence="ECO:0000305"
FT CONFLICT 1354
FT /note="S -> R (in Ref. 1; AAD08657)"
FT /evidence="ECO:0000305"
FT CONFLICT 1566
FT /note="T -> M (in Ref. 1; AAD08657)"
FT /evidence="ECO:0000305"
FT CONFLICT 1753
FT /note="K -> T (in Ref. 1; AAD08657)"
FT /evidence="ECO:0000305"
FT CONFLICT 2444
FT /note="R -> H (in Ref. 1; AAD08657)"
FT /evidence="ECO:0000305"
FT CONFLICT 2881
FT /note="C -> Y (in Ref. 1; AAD08657)"
FT /evidence="ECO:0000305"
FT CONFLICT 3070
FT /note="S -> W (in Ref. 3; AAO27475)"
FT /evidence="ECO:0000305"
FT CONFLICT 3346
FT /note="P -> R (in Ref. 3; AAO27476)"
FT /evidence="ECO:0000305"
FT CONFLICT 3583..3584
FT /note="VA -> MP (in Ref. 3; AAO27480)"
FT /evidence="ECO:0000305"
FT CONFLICT 3597
FT /note="D -> N (in Ref. 3; AAO27480)"
FT /evidence="ECO:0000305"
FT CONFLICT 3808
FT /note="F -> S (in Ref. 3; AAO27481)"
FT /evidence="ECO:0000305"
FT STRAND 425..430
FT /evidence="ECO:0007829|PDB:4L1M"
FT TURN 436..438
FT /evidence="ECO:0007829|PDB:4L1M"
FT HELIX 446..449
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 453..458
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 460..467
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 472..476
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 495..499
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 505..511
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 516..520
FT /evidence="ECO:0007829|PDB:4L1M"
FT HELIX 523..525
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 528..531
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 535..540
FT /evidence="ECO:0007829|PDB:4L1M"
FT HELIX 542..544
FT /evidence="ECO:0007829|PDB:4L1M"
FT HELIX 549..551
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 552..558
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 560..567
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 572..576
FT /evidence="ECO:0007829|PDB:4L1M"
FT HELIX 579..581
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 585..587
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 591..596
FT /evidence="ECO:0007829|PDB:4L1M"
FT HELIX 598..600
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 605..610
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 616..621
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 626..630
FT /evidence="ECO:0007829|PDB:4L1M"
FT HELIX 633..635
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 638..642
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 645..650
FT /evidence="ECO:0007829|PDB:4L1M"
FT HELIX 652..654
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 659..665
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 668..673
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 678..682
FT /evidence="ECO:0007829|PDB:4L1M"
FT HELIX 685..687
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 691..693
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 697..702
FT /evidence="ECO:0007829|PDB:4L1M"
FT HELIX 704..706
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 711..716
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 718..725
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 730..735
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 746..754
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 763..768
FT /evidence="ECO:0007829|PDB:4L1M"
FT STRAND 770..777
FT /evidence="ECO:0007829|PDB:4L1M"
FT TURN 781..783
FT /evidence="ECO:0007829|PDB:4L1M"
FT HELIX 1212..1221
FT /evidence="ECO:0007829|PDB:2KEO"
FT STRAND 1225..1228
FT /evidence="ECO:0007829|PDB:2KEO"
FT STRAND 1231..1234
FT /evidence="ECO:0007829|PDB:2KEO"
FT HELIX 1235..1242
FT /evidence="ECO:0007829|PDB:2KEO"
FT HELIX 1250..1252
FT /evidence="ECO:0007829|PDB:2KEO"
FT HELIX 1257..1266
FT /evidence="ECO:0007829|PDB:2KEO"
FT HELIX 1270..1273
FT /evidence="ECO:0007829|PDB:2KEO"
FT HELIX 1274..1277
FT /evidence="ECO:0007829|PDB:2KEO"
FT STRAND 1278..1282
FT /evidence="ECO:0007829|PDB:2KEO"
FT HELIX 1285..1288
FT /evidence="ECO:0007829|PDB:2KEO"
FT TURN 2709..2711
FT /evidence="ECO:0007829|PDB:6WW3"
FT STRAND 2714..2718
FT /evidence="ECO:0007829|PDB:6WW3"
FT STRAND 2720..2728
FT /evidence="ECO:0007829|PDB:6WW3"
FT HELIX 2733..2738
FT /evidence="ECO:0007829|PDB:6WW3"
FT STRAND 2747..2752
FT /evidence="ECO:0007829|PDB:6WW3"
FT HELIX 2782..2785
FT /evidence="ECO:0007829|PDB:7RGW"
FT STRAND 2786..2793
FT /evidence="ECO:0007829|PDB:7RGW"
FT HELIX 2795..2799
FT /evidence="ECO:0007829|PDB:7RGW"
FT HELIX 2800..2803
FT /evidence="ECO:0007829|PDB:7RGW"
FT STRAND 2818..2824
FT /evidence="ECO:0007829|PDB:7RGW"
FT STRAND 2828..2836
FT /evidence="ECO:0007829|PDB:7RGW"
FT HELIX 2839..2844
FT /evidence="ECO:0007829|PDB:7RGW"
FT STRAND 2845..2856
FT /evidence="ECO:0007829|PDB:7RGW"
FT STRAND 2861..2867
FT /evidence="ECO:0007829|PDB:7RGW"
FT STRAND 2873..2880
FT /evidence="ECO:0007829|PDB:7RGW"
FT STRAND 2886..2895
FT /evidence="ECO:0007829|PDB:7RGW"
FT HELIX 2896..2898
FT /evidence="ECO:0007829|PDB:7RGW"
FT STRAND 2906..2913
FT /evidence="ECO:0007829|PDB:7RGW"
FT STRAND 3954..3959
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 3971..3978
FT /evidence="ECO:0007829|PDB:3KCI"
FT HELIX 3980..3984
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 3987..3993
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 3996..4001
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4006..4010
FT /evidence="ECO:0007829|PDB:3KCI"
FT HELIX 4013..4015
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4018..4022
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4025..4030
FT /evidence="ECO:0007829|PDB:3KCI"
FT HELIX 4032..4034
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4039..4043
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4049..4055
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4060..4064
FT /evidence="ECO:0007829|PDB:3KCI"
FT HELIX 4067..4069
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4073..4075
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4079..4084
FT /evidence="ECO:0007829|PDB:3KCI"
FT HELIX 4086..4088
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4093..4098
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4100..4107
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4112..4116
FT /evidence="ECO:0007829|PDB:3KCI"
FT HELIX 4119..4121
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4125..4127
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4131..4136
FT /evidence="ECO:0007829|PDB:3KCI"
FT HELIX 4138..4140
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4145..4150
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4156..4161
FT /evidence="ECO:0007829|PDB:3KCI"
FT TURN 4162..4164
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4165..4170
FT /evidence="ECO:0007829|PDB:3KCI"
FT HELIX 4173..4175
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4178..4181
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4185..4190
FT /evidence="ECO:0007829|PDB:3KCI"
FT HELIX 4192..4194
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4199..4205
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4208..4213
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4218..4222
FT /evidence="ECO:0007829|PDB:3KCI"
FT HELIX 4225..4227
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4231..4233
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4237..4242
FT /evidence="ECO:0007829|PDB:3KCI"
FT HELIX 4244..4246
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4251..4256
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4258..4265
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4270..4274
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4283..4285
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4289..4294
FT /evidence="ECO:0007829|PDB:3KCI"
FT HELIX 4296..4298
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4305..4309
FT /evidence="ECO:0007829|PDB:3KCI"
FT STRAND 4312..4316
FT /evidence="ECO:0007829|PDB:3KCI"
SQ SEQUENCE 4834 AA; 527228 MW; A323DC1DA6B221D0 CRC64;
MPSESFCLAA QARLDSKWLK TDIQLAFTRD GLCGLWNEMV KDGEIVYTGT ESTQNGELPP
RKDDSVEPSG TKKEDLNDKE KKDEEETPAP IYRAKSILDS WVWGKQPDVN ELKECLSVLV
KEQQALAVQS ATTTLSALRL KQRLVILERY FIALNRTVFQ ENVKVKWKSS GISLPPVDKK
SSRPAGKGVE GLARVGSRAA LSFAFAFLRR AWRSGEDADL CSELLQESLD ALRALPEASL
FDESTVSSVW LEVVERATRF LRSVVTGDVH GTPATKGPGS IPLQDQHLAL AILLELAVQR
GTLSQMLSAI LLLLQLWDSG AQETDNERSA QGTSAPLLPL LQRFQSIICR KDAPHSEGDM
HLLSGPLSPN ESFLRYLTLP QDNELAIDLR QTAVVVMAHL DRLATPCMPP LCSSPTSHKG
SLQEVIGWGL IGWKYYANVI GPIQCEGLAN LGVTQIACAE KRFLILSRNG RVYTQAYNSD
TLAPQLVQGL ASRNIVKIAA HSDGHHYLAL AATGEVYSWG CGDGGRLGHG DTVPLEEPKV
ISAFSGKQAG KHVVHIACGS TYSAAITAEG ELYTWGRGNY GRLGHGSSED EAIPMLVAGL
KGLKVIDVAC GSGDAQTLAV TENGQVWSWG DGDYGKLGRG GSDGCKTPKL IEKLQDLDVV
KVRCGSQFSI ALTKDGQVYS WGKGDNQRLG HGTEEHVRYP KLLEGLQGKK VIDVAAGSTH
CLALTEDSEV HSWGSNDQCQ HFDTLRVTKP EPAALPGLDT KHIVGIACGP AQSFAWSSCS
EWSIGLRVPF VVDICSMTFE QLDLLLRQVS EGMDGSADWP PPQEKECVAV ATLNLLRLQL
HAAISHQVDP EFLGLGLGSI LLNSLKQTVV TLASSAGVLS TVQSAAQAVL QSGWSVLLPT
AEERARALSA LLPCAVSGNE VNISPGRRFM IDLLVGSLMA DGGLESALHA AITAEIQDIE
AKKEAQKEKE IDEQEANAST FHRSRTPLDK DLINTGICES SGKQCLPLVQ LIQQLLRNIA
SQTVARLKDV ARRISSCLDF EQHSRERSAS LDLLLRFQRL LISKLYPGES IGQTSDISSP
ELMGVGSLLK KYTALLCTHI GDILPVAASI ASTSWRHFAE VAYIVEGDFT GVLLPELVVS
IVLLLSKNAG LMQEAGAVPL LGGLLEHLDR FNHLAPGKER DDHEELAWPG IMESFFTGQN
CRNNEEVTLI RKADLENHNK DGGFWTVIDG KVYDIKDFQT QSLTGNSILA QFAGEDPVVA
LEAALQFEDT RESMHAFCVG QYLEPDQEIV TIPDLGSLSS PLIDTERNLG LLLGLHASYL
AMSTPLSPVE IECAKWLQSS IFSGGLQTSQ IHYSYNEEKD EDHCSSPGGT PASKSRLCSH
RRALGDHSQA FLQAIADNNI QDHNVKDFLC QIERYCRQCH LTTPIMFPPE HPVEEVGRLL
LCCLLKHEDL GHVALSLVHA GALGIEQVKH RTLPKSVVDV CRVVYQAKCS LIKTHQEQGR
SYKEVCAPVI ERLRFLFNEL RPAVCNDLSI MSKFKLLSSL PRWRRIAQKI IRERRKKRVP
KKPESTDDEE KIGNEESDLE EACILPHSPI NVDKRPIAIK SPKDKWQPLL STVTGVHKYK
WLKQNVQGLY PQSPLLSTIA EFALKEEPVD VEKMRKCLLK QLERAEVRLE GIDTILKLAS
KNFLLPSVQY AMFCGWQRLI PEGIDIGEPL TDCLKDVDLI PPFNRMLLEV TFGKLYAWAV
QNIRNVLMDA SAKFKELGIQ PVPLQTITNE NPSGPSLGTI PQARFLLVML SMLTLQHGAN
NLDLLLNSGM LALTQTALRL IGPSCDNVEE DMNASAQGAS ATVLEETRKE TAPVQLPVSG
PELAAMMKIG TRVMRGVDWK WGDQDGPPPG LGRVIGELGE DGWIRVQWDT GSTNSYRMGK
EGKYDLKLAE LPAAAQPSAE DSDTEDDSEA EQTERNIHPT AMMFTSTINL LQTLCLSAGV
HAEIMQSEAT KTLCGLLRML VESGTTDKTS SPNRLVYREQ HRSWCTLGFV RSIALTPQVC
GALSSPQWIT LLMKVVEGHA PFTATSLQRQ ILAVHLLQAV LPSWDKTERA RDMKCLVEKL
FDFLGSLLTT CSSDVPLLRE STLRRRRVRP QASLTATHSS TLAEEVVALL RTLHSLTQWN
GLINKYINSQ LRSITHSFVG RPSEGAQLED YFPDSENPEV GGLMAVLAVI GGIDGRLRLG
GQVMHDEFGE GTVTRITPKG KITVQFSDMR TCRVCPLNQL KPLPAVAFNV NNLPFTEPML
SVWAQLVNLA GSKLEKHKIK KSTKQAFAGQ VDLDLLRCQQ LKLYILKAGR ALLSHQDKLR
QILSQPAVQE TGTVHTDDGA VVSPDLGDMS PEGPQPPMIL LQQLLASATQ PSPVKAIFDK
QELEAAALAV CQCLAVESTH PSSPGFEDCS SSEATTPVAV QHIRPARVKR RKQSPVPALP
IVVQLMEMGF SRRNIEFALK SLTGASGNAS SLPGVEALVG WLLDHSDIQV TELSDADTVS
DEYSDEEVVE DVDDAAYSMS TGAVVTESQT YKKRADFLSN DDYAVYVREN IQVGMMVRCC
RAYEEVCEGD VGKVIKLDRD GLHDLNVQCD WQQKGGTYWV RYIHVELIGY PPPSSSSHIK
IGDKVRVKAS VTTPKYKWGS VTHQSVGVVK AFSANGKDII VDFPQQSHWT GLLSEMELVP
SIHPGVTCDG CQMFPINGSR FKCRNCDDFD FCETCFKTKK HNTRHTFGRI NEPGQSAVFC
GRSGKQLKRC HSSQPGMLLD SWSRMVKSLN VSSSVNQASR LIDGSEPCWQ SSGSQGKHWI
RLEIFPDVLV HRLKMIVDPA DSSYMPSLVV VSGGNSLNNL IELKTININP SDTTVPLLND
CTEYHRYIEI AIKQCRSSGI DCKIHGLILL GRIRAEEEDL AAVPFLASDN EEEEDEKGNS
GSLIRKKAAG LESAATIRTK VFVWGLNDKD QLGGLKGSKI KVPSFSETLS ALNVVQVAGG
SKSLFAVTVE GKVYACGEAT NGRLGLGISS GTVPIPRQIT ALSSYVVKKV AVHSGGRHAT
ALTVDGKVFS WGEGDDGKLG HFSRMNCDKP RLIEALKTKR IRDIACGSSH SAALTSSGEL
YTWGLGEYGR LGHGDNTTQL KPKMVKVLLG HRVIQVACGS RDAQTLALTD EGLVFSWGDG
DFGKLGRGGS EGCNIPQNIE RLNGQGVCQI ECGAQFSLAL TKSGVVWTWG KGDYFRLGHG
SDVHVRKPQV VEGLRGKKIV HVAVGALHCL AVTDSGQVYA WGDNDHGQQG NGTTTVNRKP
TLVQGLEGQK ITRVACGSSH SVAWTTVDVA TPSVHEPVLF QTARDPLGAS YLGVPSDADS
SAASNKISGA SNSKPNRPSL AKILLSLDGN LAKQQALSHI LTALQIMYAR DAVVGALMPA
AMIAPVECPS FSSAAPSDAS AMASPMNGEE CMLAVDIEDR LSPNPWQEKR EIVSSEDAVT
PSAVTPSAPS ASARPFIPVT DDLGAASIIA ETMTKTKEDV ESQNKAAGPE PQALDEFTSL
LIADDTRVVV DLLKLSVCSR AGDRGRDVLS AVLSGMGTAY PQVADMLLEL CVTELEDVAT
DSQSGRLSSQ PVVVESSHPY TDDTSTSGTV KIPGAEGLRV EFDRQCSTER RHDPLTVMDG
VNRIVSVRSG REWSDWSSEL RIPGDELKWK FISDGSVNGW GWRFTVYPIM PAAGPKELLS
DRCVLSCPSM DLVTCLLDFR LNLASNRSIV PRLAASLAAC AQLSALAASH RMWALQRLRK
LLTTEFGQSI NINRLLGEND GETRALSFTG SALAALVKGL PEALQRQFEY EDPIVRGGKQ
LLHSPFFKVL VALACDLELD TLPCCAETHK WAWFRRYCMA SRVAVALDKR TPLPRLFLDE
VAKKIRELMA DSENMDVLHE SHDIFKREQD EQLVQWMNRR PDDWTLSAGG SGTIYGWGHN
HRGQLGGIEG AKVKVPTPCE ALATLRPVQL IGGEQTLFAV TADGKLYATG YGAGGRLGIG
GTESVSTPTL LESIQHVFIK KVAVNSGGKH CLALSSEGEV YSWGEAEDGK LGHGNRSPCD
RPRVIESLRG IEVVDVAAGG AHSACVTAAG DLYTWGKGRY GRLGHSDSED QLKPKLVEAL
QGHRVVDIAC GSGDAQTLCL TDDDTVWSWG DGDYGKLGRG GSDGCKVPMK IDSLTGLGVV
KVECGSQFSV ALTKSGAVYT WGKGDYHRLG HGSDDHVRRP RQVQGLQGKK VIAIATGSLH
CVCCTEDGEV YTWGDNDEGQ LGDGTTNAIQ RPRLVAALQG KKVNRVACGS AHTLAWSTSK
PASAGKLPAQ VPMEYNHLQE IPIIALRNRL LLLHHLSELF CPCIPMFDLE GSLDETGLGP
SVGFDTLRGI LISQGKEAAF RKVVQATMVR DRQHGPVVEL NRIQVKRSRS KGGLAGPDGT
KSVFGQMCAK MSSFGPDSLL LPHRVWKVKF VGESVDDCGG GYSESIAEIC EELQNGLTPL
LIVTPNGRDE SGANRDCYLL SPAARAPVHS SMFRFLGVLL GIAIRTGSPL SLNLAEPVWK
QLAGMSLTIA DLSEVDKDFI PGLMYIRDNE ATSEEFEAMS LPFTVPSASG QDIQLSSKHT
HITLDNRAEY VRLAINYRLH EFDEQVAAVR EGMARVVPVP LLSLFTGYEL ETMVCGSPDI
PLHLLKSVAT YKGIEPSASL IQWFWEVMES FSNTERSLFL RFVWGRTRLP RTIADFRGRD
FVIQVLDKYN PPDHFLPESY TCFFLLKLPR YSCKQVLEEK LKYAIHFCKS IDTDDYARIA
LTGEPAADDS SDDSDNEDVD SFASDSTQDY LTGH
//
