JMJD6_HUMAN
ID JMJD6_HUMAN Reviewed; 403 AA.
AC Q6NYC1; B3KMN8; B4DGX1; Q86VY0; Q8IUM5; Q9Y4E2;
DT 07-JUN-2005, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 164.
DE RecName: Full=Bifunctional arginine demethylase and lysyl-hydroxylase JMJD6 {ECO:0000305};
DE EC=1.14.11.- {ECO:0000269|PubMed:17947579, ECO:0000269|PubMed:19574390, ECO:0000269|PubMed:20684070, ECO:0000269|PubMed:22189873};
DE AltName: Full=Histone arginine demethylase JMJD6;
DE AltName: Full=JmjC domain-containing protein 6;
DE AltName: Full=Jumonji domain-containing protein 6;
DE AltName: Full=Lysyl-hydroxylase JMJD6;
DE AltName: Full=Peptide-lysine 5-dioxygenase JMJD6;
DE AltName: Full=Phosphatidylserine receptor;
DE Short=Protein PTDSR;
GN Name=JMJD6 {ECO:0000312|HGNC:HGNC:19355};
GN Synonyms=KIAA0585, PSR {ECO:0000303|PubMed:14729065}, PTDSR;
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 [MRNA] (ISOFORM 2).
RC TISSUE=Stomach cancer;
RA Izawa M., Takahashi M.;
RT "Identification of an alternative form of phosphatidylserine receptor.";
RL Submitted (OCT-2001) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3), AND TISSUE SPECIFICITY.
RC TISSUE=Brain;
RX PubMed=9628581; DOI=10.1093/dnares/5.1.31;
RA Nagase T., Ishikawa K., Miyajima N., Tanaka A., Kotani H., Nomura N.,
RA Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. IX. The
RT complete sequences of 100 new cDNA clones from brain which can code for
RT large proteins in vitro.";
RL DNA Res. 5:31-39(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3).
RC TISSUE=Brain, and Embryo;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S.,
RA Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E.,
RA Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K.,
RA LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J.,
RA Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A.,
RA Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K.,
RA Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in the
RT human lineage.";
RL Nature 440:1045-1049(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Skin, 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 [7]
RP SUBCELLULAR LOCATION, AND NUCLEAR LOCALIZATION SIGNALS.
RX PubMed=14729065; DOI=10.1016/j.yexcr.2003.09.023;
RA Cui P., Qin B., Liu N., Pan G., Pei D.;
RT "Nuclear localization of the phosphatidylserine receptor protein via
RT multiple nuclear localization signals.";
RL Exp. Cell Res. 293:154-163(2004).
RN [8]
RP TISSUE SPECIFICITY, AND INDUCTION.
RX PubMed=15072554; DOI=10.1677/jme.0.0320497;
RA Cao W.M., Murao K., Imachi H., Hiramine C., Abe H., Yu X., Dobashi H.,
RA Wong N.C.W., Takahara J., Ishida T.;
RT "Phosphatidylserine receptor cooperates with high-density lipoprotein
RT receptor in recognition of apoptotic cells by thymic nurse cells.";
RL J. Mol. Endocrinol. 32:497-505(2004).
RN [9]
RP TISSUE SPECIFICITY, AND POSSIBLE FUNCTION.
RX PubMed=15622002; DOI=10.1097/01.sla.0000149304.89456.5a;
RA Koeninger J., Balaz P., Wagner M., Shi X., Cima I., Zimmermann A.,
RA di Sebastiano P., Buechler M.W., Friess H.;
RT "Phosphatidylserine receptor in chronic pancreatitis: evidence for a
RT macrophage independent role.";
RL Ann. Surg. 241:144-151(2005).
RN [10]
RP FUNCTION AS HISTONE DEMETHYLASE, MUTAGENESIS OF HIS-187; ASP-189 AND
RP HIS-273, AND CATALYTIC ACTIVITY.
RX PubMed=17947579; DOI=10.1126/science.1145801;
RA Chang B., Chen Y., Zhao Y., Bruick R.K.;
RT "JMJD6 is a histone arginine demethylase.";
RL Science 318:444-447(2007).
RN [11]
RP FUNCTION AS LYSYL-HYDROXYLASE, COFACTOR, INTERACTION WITH LUC7L2; LUC7L3
RP AND U2AF2, MUTAGENESIS OF HIS-187 AND ASP-189, AND CATALYTIC ACTIVITY.
RX PubMed=19574390; DOI=10.1126/science.1175865;
RA Webby C.J., Wolf A., Gromak N., Dreger M., Kramer H., Kessler B.,
RA Nielsen M.L., Schmitz C., Butler D.S., Yates J.R. III, Delahunty C.M.,
RA Hahn P., Lengeling A., Mann M., Proudfoot N.J., Schofield C.J.,
RA Boettger A.;
RT "Jmjd6 catalyses lysyl-hydroxylation of U2AF65, a protein associated with
RT RNA splicing.";
RL Science 325:90-93(2009).
RN [12]
RP SUBCELLULAR LOCATION, RNA-BINDING, AND FUNCTION.
RX PubMed=21060799; DOI=10.1371/journal.pone.0013769;
RA Hahn P., Wegener I., Burrells A., Bose J., Wolf A., Erck C., Butler D.,
RA Schofield C.J., Bottger A., Lengeling A.;
RT "Analysis of Jmjd6 cellular localization and testing for its involvement in
RT histone demethylation.";
RL PLoS ONE 5:E13769-E13769(2010).
RN [13]
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 [14]
RP INTERACTION WITH BRD4.
RX PubMed=21555454; DOI=10.1128/mcb.01341-10;
RA Rahman S., Sowa M.E., Ottinger M., Smith J.A., Shi Y., Harper J.W.,
RA Howley P.M.;
RT "The Brd4 extraterminal domain confers transcription activation independent
RT of pTEFb by recruiting multiple proteins, including NSD3.";
RL Mol. Cell. Biol. 31:2641-2652(2011).
RN [15]
RP FUNCTION, MUTAGENESIS OF HIS-187, CATALYTIC ACTIVITY, COFACTOR, AND
RP SUBUNIT.
RX PubMed=22189873; DOI=10.1002/jcb.24035;
RA Han G., Li J., Wang Y., Li X., Mao H., Liu Y., Chen C.D.;
RT "The hydroxylation activity of Jmjd6 is required for its homo-
RT oligomerization.";
RL J. Cell. Biochem. 113:1663-1670(2012).
RN [16]
RP FUNCTION, INTERACTION WITH BRD4; CDK9 AND CCNT1, CATALYTIC ACTIVITY,
RP MUTAGENESIS OF HIS-187, AND SUBUNIT.
RX PubMed=24360279; DOI=10.1016/j.cell.2013.10.056;
RA Liu W., Ma Q., Wong K., Li W., Ohgi K., Zhang J., Aggarwal A.,
RA Rosenfeld M.G.;
RT "Brd4 and JMJD6-associated anti-pause enhancers in regulation of
RT transcriptional pause release.";
RL Cell 155:1581-1595(2013).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-38, AND IDENTIFICATION BY
RP 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 [18]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=24498420; DOI=10.1371/journal.pone.0087982;
RA Poulard C., Rambaud J., Hussein N., Corbo L., Le Romancer M.;
RT "JMJD6 regulates ERalpha methylation on arginine.";
RL PLoS ONE 9:E87982-E87982(2014).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF 1-335 IN COMPLEX WITH NICKEL
RP IONS, FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, MUTAGENESIS OF TYR-131;
RP LYS-204; GLU-231; THR-285 AND ASN-287, AND CATALYTIC ACTIVITY.
RX PubMed=20684070; DOI=10.1016/j.jmb.2010.05.054;
RA Mantri M., Krojer T., Bagg E.A., Webby C.J., Butler D.S., Kochan G.,
RA Kavanagh K.L., Oppermann U., McDonough M.A., Schofield C.J.;
RT "Crystal structure of the 2-oxoglutarate- and Fe(II)-dependent lysyl
RT hydroxylase JMJD6.";
RL J. Mol. Biol. 401:211-222(2010).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 1-334 IN COMPLEX WITH IRON IONS
RP AND 2-OXOGLUTARATE, POSSIBLE FUNCTION, AND RNA-BINDING.
RX PubMed=20679243; DOI=10.1073/pnas.1008832107;
RA Hong X., Zang J., White J., Wang C., Pan C.H., Zhao R., Murphy R.C.,
RA Dai S., Henson P., Kappler J.W., Hagman J., Zhang G.;
RT "Interaction of JMJD6 with single-stranded RNA.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:14568-14572(2010).
RN [21] {ECO:0007744|PDB:6BNH}
RP STRUCTURE BY NMR OF 84-96 IN COMPLEX WITH BRD4, INTERACTION WITH BRD4,
RP SSRNA-BINDING, AND MUTAGENESIS OF TRP-85; LEU-90; LYS-91 AND ARG-95.
RX PubMed=29176719; DOI=10.1038/s41598-017-16588-8;
RA Konuma T., Yu D., Zhao C., Ju Y., Sharma R., Ren C., Zhang Q., Zhou M.M.,
RA Zeng L.;
RT "Structural Mechanism of the Oxygenase JMJD6 Recognition by the
RT Extraterminal (ET) Domain of BRD4.";
RL Sci. Rep. 7:16272-16272(2017).
CC -!- FUNCTION: Dioxygenase that can both act as a arginine demethylase and a
CC lysyl-hydroxylase (PubMed:24498420, PubMed:17947579, PubMed:20684070,
CC PubMed:21060799, PubMed:22189873). Acts as a lysyl-hydroxylase that
CC catalyzes 5-hydroxylation on specific lysine residues of target
CC proteins such as U2AF2/U2AF65 and LUC7L2. Regulates RNA splicing by
CC mediating 5-hydroxylation of U2AF2/U2AF65, affecting the pre-mRNA
CC splicing activity of U2AF2/U2AF65 (PubMed:19574390). Hydroxylates its
CC own N-terminus, which is required for homooligomerization
CC (PubMed:22189873). In addition to peptidyl-lysine 5-dioxygenase
CC activity, may act as an RNA hydroxylase, as suggested by its ability to
CC bind single strand RNA (PubMed:20679243, PubMed:29176719). Also acts as
CC an arginine demethylase which preferentially demethylates asymmetric
CC dimethylation (PubMed:17947579, PubMed:24498420, PubMed:24360279).
CC Demethylates histone H3 at 'Arg-2' (H3R2me) and histone H4 at 'Arg-3'
CC (H4R3me), including mono-, symmetric di- and asymmetric dimethylated
CC forms, thereby playing a role in histone code (PubMed:17947579,
CC PubMed:24360279). However, histone arginine demethylation may not
CC constitute the primary activity in vivo (PubMed:17947579,
CC PubMed:21060799, PubMed:22189873). In collaboration with BRD4,
CC interacts with the positive transcription elongation factor b (P-TEFb)
CC complex in its active form to regulate polymerase II promoter-proximal
CC pause release for transcriptional activation of a large cohort of
CC genes. On distal enhancers, so called anti-pause enhancers,
CC demethylates both histone H4R3me2 and the methyl cap of 7SKsnRNA
CC leading to the dismissal of the 7SKsnRNA:HEXIM1 inhibitor complex.
CC After removal of repressive marks, the complex BRD4:JMJD6 attract and
CC retain the P-TEFb complex on chromatin, leading to its activation,
CC promoter-proximal polymerase II pause release, and transcriptional
CC activation (PubMed:24360279). Demethylates other arginine methylated-
CC proteins such as ESR1 (PubMed:24498420). Has no histone lysine
CC demethylase activity (PubMed:21060799). Required for differentiation of
CC multiple organs during embryogenesis. Acts as a key regulator of
CC hematopoietic differentiation: required for angiogenic sprouting by
CC regulating the pre-mRNA splicing activity of U2AF2/U2AF65 (By
CC similarity). Seems to be necessary for the regulation of macrophage
CC cytokine responses (PubMed:15622002). {ECO:0000250|UniProtKB:Q9ERI5,
CC ECO:0000269|PubMed:15622002, ECO:0000269|PubMed:17947579,
CC ECO:0000269|PubMed:19574390, ECO:0000269|PubMed:20679243,
CC ECO:0000269|PubMed:20684070, ECO:0000269|PubMed:21060799,
CC ECO:0000269|PubMed:22189873, ECO:0000269|PubMed:24360279,
CC ECO:0000269|PubMed:24498420, ECO:0000269|PubMed:29176719}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-oxoglutarate + L-lysyl-[protein] + O2 = (5S)-5-hydroxy-L-
CC lysyl-[protein] + CO2 + succinate; Xref=Rhea:RHEA:58360, Rhea:RHEA-
CC COMP:9752, Rhea:RHEA-COMP:15144, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:29969,
CC ChEBI:CHEBI:30031, ChEBI:CHEBI:141843;
CC Evidence={ECO:0000269|PubMed:19574390, ECO:0000269|PubMed:20684070,
CC ECO:0000269|PubMed:22189873};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 2-oxoglutarate + N(omega),N(omega)'-dimethyl-L-arginyl-
CC [protein] + 2 O2 = 2 CO2 + 2 formaldehyde + L-arginyl-[protein] + 2
CC succinate; Xref=Rhea:RHEA:58348, Rhea:RHEA-COMP:10532, Rhea:RHEA-
CC COMP:11992, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810,
CC ChEBI:CHEBI:16842, ChEBI:CHEBI:29965, ChEBI:CHEBI:30031,
CC ChEBI:CHEBI:88221; Evidence={ECO:0000269|PubMed:17947579,
CC ECO:0000269|PubMed:24360279};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-oxoglutarate + N(omega),N(omega)'-dimethyl-L-arginyl-
CC [protein] + O2 = CO2 + formaldehyde + N(omega)-methyl-L-arginyl-
CC [protein] + succinate; Xref=Rhea:RHEA:58472, Rhea:RHEA-COMP:11990,
CC Rhea:RHEA-COMP:11992, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526,
CC ChEBI:CHEBI:16810, ChEBI:CHEBI:16842, ChEBI:CHEBI:30031,
CC ChEBI:CHEBI:65280, ChEBI:CHEBI:88221;
CC Evidence={ECO:0000269|PubMed:17947579, ECO:0000269|PubMed:24360279};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-oxoglutarate + a 5'-end methyltriphosphate-guanosine-
CC ribonucleotide-snRNA + O2 = a 5'-end triphospho-guanosine-
CC ribonucleotide-snRNA + CO2 + formaldehyde + H(+) + succinate;
CC Xref=Rhea:RHEA:58784, Rhea:RHEA-COMP:15220, Rhea:RHEA-COMP:15221,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526,
CC ChEBI:CHEBI:16810, ChEBI:CHEBI:16842, ChEBI:CHEBI:30031,
CC ChEBI:CHEBI:138278, ChEBI:CHEBI:142789;
CC Evidence={ECO:0000269|PubMed:24360279};
CC -!- COFACTOR:
CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033;
CC Evidence={ECO:0000269|PubMed:19574390, ECO:0000269|PubMed:22189873};
CC Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000269|PubMed:19574390};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=39 uM for 2-oxoglutarate {ECO:0000269|PubMed:20684070};
CC -!- SUBUNIT: Homooligomerizes; requires lysyl-hydroxylase activity
CC (PubMed:22189873, PubMed:24360279). Interacts with LUC7L2, LUC7L3 and
CC U2AF2/U2AF65 (PubMed:19574390). Interacts with LIAT1 (By similarity).
CC Interacts with CDK9 and CCNT1; the interaction is direct with CDK9 and
CC associates the P-TEFb complex when active (PubMed:24360279). Interacts
CC (via JmjC and N-terminal domains) with BRD4 (via NET domain); the
CC interaction is stronger in presence of ssRNA and recruits JMJD6 on
CC distal enhancers (PubMed:21555454, PubMed:24360279, PubMed:29176719).
CC {ECO:0000250|UniProtKB:Q9ERI5, ECO:0000269|PubMed:19574390,
CC ECO:0000269|PubMed:21555454, ECO:0000269|PubMed:22189873,
CC ECO:0000269|PubMed:24360279, ECO:0000269|PubMed:29176719}.
CC -!- INTERACTION:
CC Q6NYC1; O60885: BRD4; NbExp=10; IntAct=EBI-8464037, EBI-723869;
CC Q6NYC1; Q86X55: CARM1; NbExp=2; IntAct=EBI-8464037, EBI-2339854;
CC Q6NYC1; P50750: CDK9; NbExp=5; IntAct=EBI-8464037, EBI-1383449;
CC Q6NYC1; P03372: ESR1; NbExp=8; IntAct=EBI-8464037, EBI-78473;
CC Q6NYC1; Q96NE9: FRMD6; NbExp=3; IntAct=EBI-8464037, EBI-741729;
CC Q6NYC1; Q6NYC1: JMJD6; NbExp=3; IntAct=EBI-8464037, EBI-8464037;
CC Q6NYC1; Q9GZZ1: NAA50; NbExp=6; IntAct=EBI-8464037, EBI-1052523;
CC Q6NYC1; Q8NAV1: PRPF38A; NbExp=2; IntAct=EBI-8464037, EBI-715374;
CC Q6NYC1; P04637: TP53; NbExp=7; IntAct=EBI-8464037, EBI-366083;
CC Q6NYC1; Q01081: U2AF1; NbExp=2; IntAct=EBI-8464037, EBI-632461;
CC Q6NYC1; Q9NP64: ZCCHC17; NbExp=2; IntAct=EBI-8464037, EBI-746345;
CC -!- SUBCELLULAR LOCATION: Nucleus, nucleoplasm
CC {ECO:0000269|PubMed:14729065, ECO:0000269|PubMed:21060799}. Nucleus,
CC nucleolus {ECO:0000269|PubMed:21060799}. Cytoplasm
CC {ECO:0000269|PubMed:21060799, ECO:0000269|PubMed:24498420}. Note=Mainly
CC found throughout the nucleoplasm outside of regions containing
CC heterochromatic DNA, with some localization in nucleolus. During
CC mitosis, excluded from the nucleus and reappears in the telophase of
CC the cell cycle. {ECO:0000269|PubMed:21060799}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=Alpha;
CC IsoId=Q6NYC1-1; Sequence=Displayed;
CC Name=2; Synonyms=Beta;
CC IsoId=Q6NYC1-2; Sequence=VSP_014022, VSP_014023;
CC Name=3;
CC IsoId=Q6NYC1-3; Sequence=VSP_014023;
CC -!- TISSUE SPECIFICITY: Highly expressed in the heart, skeletal muscle and
CC kidney. Expressed at moderate or low level in brain, placenta, lung,
CC liver, pancreas, spleen, thymus, prostate, testis and ovary. Up-
CC regulated in many patients with chronic pancreatitis. Expressed in
CC nursing thymic epithelial cells. {ECO:0000269|PubMed:15072554,
CC ECO:0000269|PubMed:15622002, ECO:0000269|PubMed:9628581}.
CC -!- INDUCTION: Up-regulated upon cytokine treatment, but not upon TNF
CC treatment. {ECO:0000269|PubMed:15072554}.
CC -!- DOMAIN: The nuclear localization signal motifs are necessary and
CC sufficient to target it into the nucleus.
CC {ECO:0000269|PubMed:14729065}.
CC -!- PTM: Hydroxylates its own N-terminus; hydroxylation is required for
CC homooligomerization. {ECO:0000269|PubMed:22189873}.
CC -!- SIMILARITY: Belongs to the JMJD6 family. {ECO:0000305}.
CC -!- CAUTION: Was initially thought to constitute the phosphatidylserine
CC receptor, a receptor that mediates recognition of phosphatidylserine, a
CC specific marker only present at the surface of apoptotic cells.
CC Phosphatidylserine receptor probably participates in apoptotic cell
CC phagocytosis. This protein was identified using phage display
CC expressing mAb 217, an antibody that specifically recognizes
CC phosphatidylserine receptor. However, its nuclear localization and the
CC fact that mAb 217 antibody still recognizes the phosphatidylserine
CC receptor in mice lacking JMJD6, strongly suggest that it does not
CC constitute the receptor for phosphatidylserine and is not involved in
CC apoptotic cell removal. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH47003.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAA25511.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AB073711; BAC16755.1; -; mRNA.
DR EMBL; AB011157; BAA25511.1; ALT_INIT; mRNA.
DR EMBL; AK021780; BAG51050.1; -; mRNA.
DR EMBL; AK294816; BAG57932.1; -; mRNA.
DR EMBL; AC005837; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471099; EAW89434.1; -; Genomic_DNA.
DR EMBL; BC047003; AAH47003.1; ALT_INIT; mRNA.
DR EMBL; BC066654; AAH66654.1; -; mRNA.
DR CCDS; CCDS42383.1; -. [Q6NYC1-3]
DR CCDS; CCDS42384.1; -. [Q6NYC1-1]
DR RefSeq; NP_001074930.1; NM_001081461.1. [Q6NYC1-3]
DR RefSeq; NP_055982.2; NM_015167.2. [Q6NYC1-1]
DR PDB; 3K2O; X-ray; 1.75 A; A/B=2-335.
DR PDB; 3LD8; X-ray; 2.70 A; A=1-334.
DR PDB; 3LDB; X-ray; 2.70 A; A=1-334.
DR PDB; 6BNH; NMR; -; B=84-96.
DR PDB; 6GDY; X-ray; 2.04 A; A/B=1-343.
DR PDB; 6MEV; X-ray; 2.60 A; A/B/C/D/E/F/G/H=1-341.
DR PDBsum; 3K2O; -.
DR PDBsum; 3LD8; -.
DR PDBsum; 3LDB; -.
DR PDBsum; 6BNH; -.
DR PDBsum; 6GDY; -.
DR PDBsum; 6MEV; -.
DR AlphaFoldDB; Q6NYC1; -.
DR SMR; Q6NYC1; -.
DR BioGRID; 116817; 184.
DR DIP; DIP-60686N; -.
DR IntAct; Q6NYC1; 144.
DR MINT; Q6NYC1; -.
DR STRING; 9606.ENSP00000394085; -.
DR BindingDB; Q6NYC1; -.
DR ChEMBL; CHEMBL4523345; -.
DR GlyGen; Q6NYC1; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q6NYC1; -.
DR PhosphoSitePlus; Q6NYC1; -.
DR BioMuta; JMJD6; -.
DR DMDM; 67461014; -.
DR EPD; Q6NYC1; -.
DR jPOST; Q6NYC1; -.
DR MassIVE; Q6NYC1; -.
DR MaxQB; Q6NYC1; -.
DR PaxDb; Q6NYC1; -.
DR PeptideAtlas; Q6NYC1; -.
DR PRIDE; Q6NYC1; -.
DR ProteomicsDB; 66781; -. [Q6NYC1-1]
DR ProteomicsDB; 66782; -. [Q6NYC1-2]
DR ProteomicsDB; 66783; -. [Q6NYC1-3]
DR ABCD; Q6NYC1; 4 sequenced antibodies.
DR Antibodypedia; 3874; 448 antibodies from 41 providers.
DR DNASU; 23210; -.
DR Ensembl; ENST00000397625.9; ENSP00000380750.4; ENSG00000070495.15. [Q6NYC1-1]
DR Ensembl; ENST00000445478.6; ENSP00000394085.2; ENSG00000070495.15. [Q6NYC1-3]
DR GeneID; 23210; -.
DR KEGG; hsa:23210; -.
DR MANE-Select; ENST00000397625.9; ENSP00000380750.4; NM_015167.3; NP_055982.2.
DR UCSC; uc002jsn.2; human. [Q6NYC1-1]
DR CTD; 23210; -.
DR DisGeNET; 23210; -.
DR GeneCards; JMJD6; -.
DR HGNC; HGNC:19355; JMJD6.
DR HPA; ENSG00000070495; Tissue enhanced (bone).
DR MIM; 604914; gene.
DR neXtProt; NX_Q6NYC1; -.
DR OpenTargets; ENSG00000070495; -.
DR PharmGKB; PA162392513; -.
DR VEuPathDB; HostDB:ENSG00000070495; -.
DR eggNOG; KOG2130; Eukaryota.
DR GeneTree; ENSGT00940000156867; -.
DR HOGENOM; CLU_016785_8_0_1; -.
DR InParanoid; Q6NYC1; -.
DR OMA; DLFKYCG; -.
DR OrthoDB; 609279at2759; -.
DR PhylomeDB; Q6NYC1; -.
DR TreeFam; TF314988; -.
DR BRENDA; 1.14.11.4; 2681.
DR PathwayCommons; Q6NYC1; -.
DR Reactome; R-HSA-3214842; HDMs demethylate histones.
DR SABIO-RK; Q6NYC1; -.
DR SignaLink; Q6NYC1; -.
DR SIGNOR; Q6NYC1; -.
DR BioGRID-ORCS; 23210; 269 hits in 1101 CRISPR screens.
DR ChiTaRS; JMJD6; human.
DR EvolutionaryTrace; Q6NYC1; -.
DR GeneWiki; JMJD6; -.
DR GenomeRNAi; 23210; -.
DR Pharos; Q6NYC1; Tchem.
DR PRO; PR:Q6NYC1; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; Q6NYC1; protein.
DR Bgee; ENSG00000070495; Expressed in saphenous vein and 209 other tissues.
DR ExpressionAtlas; Q6NYC1; baseline and differential.
DR Genevisible; Q6NYC1; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR GO; GO:0005730; C:nucleolus; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IEA:Ensembl.
DR GO; GO:1990904; C:ribonucleoprotein complex; IEA:Ensembl.
DR GO; GO:0032451; F:demethylase activity; IDA:UniProtKB.
DR GO; GO:0032452; F:histone demethylase activity; IDA:UniProtKB.
DR GO; GO:0033746; F:histone H3-methyl-arginine-2 demethylase activity; IDA:UniProtKB.
DR GO; GO:0033749; F:histone H3-methyl-arginine-3 demethylase activity; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IDA:BHF-UCL.
DR GO; GO:0005506; F:iron ion binding; IDA:UniProtKB.
DR GO; GO:0035515; F:oxidative RNA demethylase activity; IMP:UniProtKB.
DR GO; GO:0106140; F:P-TEFb complex binding; IDA:UniProtKB.
DR GO; GO:0070815; F:peptidyl-lysine 5-dioxygenase activity; IDA:UniProtKB.
DR GO; GO:0003723; F:RNA binding; TAS:UniProtKB.
DR GO; GO:0038023; F:signaling receptor activity; IEA:Ensembl.
DR GO; GO:0003727; F:single-stranded RNA binding; IDA:UniProtKB.
DR GO; GO:0140537; F:transcription regulator activator activity; IMP:UniProtKB.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0006325; P:chromatin organization; IEA:UniProtKB-KW.
DR GO; GO:0048821; P:erythrocyte development; IEA:Ensembl.
DR GO; GO:0007507; P:heart development; IEA:Ensembl.
DR GO; GO:0070078; P:histone H3-R2 demethylation; IDA:BHF-UCL.
DR GO; GO:0070079; P:histone H4-R3 demethylation; IDA:UniProtKB.
DR GO; GO:0001822; P:kidney development; IEA:Ensembl.
DR GO; GO:0030324; P:lung development; IEA:Ensembl.
DR GO; GO:0042116; P:macrophage activation; IEA:Ensembl.
DR GO; GO:0006397; P:mRNA processing; IEA:UniProtKB-KW.
DR GO; GO:0035513; P:oxidative RNA demethylation; IDA:UniProtKB.
DR GO; GO:0018395; P:peptidyl-lysine hydroxylation to 5-hydroxy-L-lysine; IDA:UniProtKB.
DR GO; GO:0006909; P:phagocytosis; IBA:GO_Central.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IMP:UniProtKB.
DR GO; GO:0006482; P:protein demethylation; IDA:UniProtKB.
DR GO; GO:0051260; P:protein homooligomerization; IDA:UniProtKB.
DR GO; GO:0043654; P:recognition of apoptotic cell; IEA:Ensembl.
DR GO; GO:0048024; P:regulation of mRNA splicing, via spliceosome; IMP:UniProtKB.
DR GO; GO:0060041; P:retina development in camera-type eye; IEA:Ensembl.
DR GO; GO:0008380; P:RNA splicing; IEA:UniProtKB-KW.
DR GO; GO:0002040; P:sprouting angiogenesis; ISS:UniProtKB.
DR GO; GO:0033077; P:T cell differentiation in thymus; IEA:Ensembl.
DR InterPro; IPR003347; JmjC_dom.
DR Pfam; PF02373; JmjC; 1.
DR SMART; SM00558; JmjC; 1.
DR PROSITE; PS51184; JMJC; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Chromatin regulator; Cytoplasm;
KW Developmental protein; Differentiation; Dioxygenase; Iron; Metal-binding;
KW mRNA processing; mRNA splicing; Nucleus; Oxidoreductase; Phosphoprotein;
KW Reference proteome; RNA-binding; Transcription; Transcription regulation.
FT CHAIN 1..403
FT /note="Bifunctional arginine demethylase and lysyl-
FT hydroxylase JMJD6"
FT /id="PRO_0000129369"
FT DOMAIN 141..305
FT /note="JmjC"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00538"
FT REGION 336..403
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 6..10
FT /note="Nuclear localization signal 1"
FT /evidence="ECO:0000269|PubMed:14729065"
FT MOTIF 91..95
FT /note="Nuclear localization signal 2"
FT /evidence="ECO:0000269|PubMed:14729065"
FT MOTIF 141..145
FT /note="Nuclear localization signal 3"
FT /evidence="ECO:0000269|PubMed:14729065"
FT MOTIF 167..170
FT /note="Nuclear localization signal 4"
FT /evidence="ECO:0000269|PubMed:14729065"
FT MOTIF 373..378
FT /note="Nuclear localization signal 5"
FT /evidence="ECO:0000269|PubMed:14729065"
FT COMPBIAS 336..360
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 184
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 187
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:20679243"
FT BINDING 189
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:20679243"
FT BINDING 197
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000269|PubMed:20679243"
FT BINDING 204
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 273
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:20679243"
FT BINDING 285
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000269|PubMed:20679243"
FT MOD_RES 38
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VAR_SEQ 361..402
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|Ref.1"
FT /id="VSP_014022"
FT VAR_SEQ 403
FT /note="R -> RIRDTCGGRAHP (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:9628581, ECO:0000303|Ref.1"
FT /id="VSP_014023"
FT MUTAGEN 85
FT /note="W->A: Decreases interaction with the NET domain of
FT BRD4."
FT /evidence="ECO:0000269|PubMed:29176719"
FT MUTAGEN 90
FT /note="L->A: Nearly abolishes the interaction with the NET
FT domain of BRD4."
FT /evidence="ECO:0000269|PubMed:29176719"
FT MUTAGEN 91
FT /note="K->A: Nearly abolishes the interaction with the NET
FT domain of BRD4."
FT /evidence="ECO:0000269|PubMed:29176719"
FT MUTAGEN 95
FT /note="R->A: Nearly abolishes the interaction with the NET
FT domain of BRD4."
FT /evidence="ECO:0000269|PubMed:29176719"
FT MUTAGEN 131
FT /note="Y->F: Abolishes 2-oxoglutarate-binding and enzyme
FT activity."
FT /evidence="ECO:0000269|PubMed:20684070"
FT MUTAGEN 187
FT /note="H->A: Loss of histone arginine demethylase and
FT lysyl-hydroxylase activities. Abolishes
FT homooligomerisation. Loss of arginine demethylase and a
FT lysyl-hydroxylase activities; when associated with A-189
FT and A-273."
FT /evidence="ECO:0000269|PubMed:17947579,
FT ECO:0000269|PubMed:19574390, ECO:0000269|PubMed:22189873,
FT ECO:0000269|PubMed:24360279"
FT MUTAGEN 189
FT /note="D->A: Loss of arginine demethylase and a lysyl-
FT hydroxylase activities; when associated with A-187 and A-
FT 273."
FT /evidence="ECO:0000269|PubMed:17947579,
FT ECO:0000269|PubMed:19574390"
FT MUTAGEN 204
FT /note="K->A: Impairs enzyme activity without affecting 2-
FT oxoglutarate-binding."
FT /evidence="ECO:0000269|PubMed:20684070"
FT MUTAGEN 231
FT /note="E->A: Impairs both hydroxylation activity and 2-
FT oxoglutarate turnover assays."
FT /evidence="ECO:0000269|PubMed:20684070"
FT MUTAGEN 273
FT /note="H->A: Loss of arginine demethylase and a lysyl-
FT hydroxylase activities; when associated with A-187 and A-
FT 189."
FT /evidence="ECO:0000269|PubMed:17947579"
FT MUTAGEN 285
FT /note="T->A: Impairs enzyme activity and 2-oxoglutarate-
FT binding."
FT /evidence="ECO:0000269|PubMed:20684070"
FT MUTAGEN 287
FT /note="N->A: Impairs enzyme activity."
FT /evidence="ECO:0000269|PubMed:20684070"
FT CONFLICT 136
FT /note="S -> G (in Ref. 3; BAG51050)"
FT /evidence="ECO:0000305"
FT HELIX 3..16
FT /evidence="ECO:0007829|PDB:3K2O"
FT HELIX 23..27
FT /evidence="ECO:0007829|PDB:3K2O"
FT HELIX 31..34
FT /evidence="ECO:0007829|PDB:3K2O"
FT HELIX 39..41
FT /evidence="ECO:0007829|PDB:3K2O"
FT STRAND 48..50
FT /evidence="ECO:0007829|PDB:3K2O"
FT HELIX 51..53
FT /evidence="ECO:0007829|PDB:3K2O"
FT HELIX 56..62
FT /evidence="ECO:0007829|PDB:3K2O"
FT TURN 63..67
FT /evidence="ECO:0007829|PDB:3K2O"
FT STRAND 70..74
FT /evidence="ECO:0007829|PDB:3K2O"
FT TURN 75..78
FT /evidence="ECO:0007829|PDB:3K2O"
FT HELIX 81..84
FT /evidence="ECO:0007829|PDB:3K2O"
FT HELIX 87..93
FT /evidence="ECO:0007829|PDB:3K2O"
FT TURN 94..96
FT /evidence="ECO:0007829|PDB:6GDY"
FT STRAND 98..103
FT /evidence="ECO:0007829|PDB:3K2O"
FT STRAND 109..113
FT /evidence="ECO:0007829|PDB:3K2O"
FT HELIX 114..123
FT /evidence="ECO:0007829|PDB:3K2O"
FT STRAND 132..135
FT /evidence="ECO:0007829|PDB:3K2O"
FT HELIX 137..139
FT /evidence="ECO:0007829|PDB:3K2O"
FT HELIX 143..149
FT /evidence="ECO:0007829|PDB:3K2O"
FT HELIX 154..156
FT /evidence="ECO:0007829|PDB:3K2O"
FT HELIX 160..164
FT /evidence="ECO:0007829|PDB:3K2O"
FT TURN 166..168
FT /evidence="ECO:0007829|PDB:3K2O"
FT STRAND 173..178
FT /evidence="ECO:0007829|PDB:3K2O"
FT STRAND 183..187
FT /evidence="ECO:0007829|PDB:3K2O"
FT HELIX 190..192
FT /evidence="ECO:0007829|PDB:3K2O"
FT STRAND 194..202
FT /evidence="ECO:0007829|PDB:3K2O"
FT STRAND 204..209
FT /evidence="ECO:0007829|PDB:3K2O"
FT HELIX 215..218
FT /evidence="ECO:0007829|PDB:3K2O"
FT HELIX 222..225
FT /evidence="ECO:0007829|PDB:3K2O"
FT HELIX 226..228
FT /evidence="ECO:0007829|PDB:3K2O"
FT HELIX 232..238
FT /evidence="ECO:0007829|PDB:3K2O"
FT HELIX 240..244
FT /evidence="ECO:0007829|PDB:3K2O"
FT HELIX 250..252
FT /evidence="ECO:0007829|PDB:3K2O"
FT STRAND 255..259
FT /evidence="ECO:0007829|PDB:3K2O"
FT STRAND 264..267
FT /evidence="ECO:0007829|PDB:3K2O"
FT STRAND 272..279
FT /evidence="ECO:0007829|PDB:3K2O"
FT STRAND 281..288
FT /evidence="ECO:0007829|PDB:3K2O"
FT TURN 291..293
FT /evidence="ECO:0007829|PDB:3K2O"
FT HELIX 294..304
FT /evidence="ECO:0007829|PDB:3K2O"
FT HELIX 306..319
FT /evidence="ECO:0007829|PDB:3K2O"
FT HELIX 321..333
FT /evidence="ECO:0007829|PDB:3K2O"
SQ SEQUENCE 403 AA; 46462 MW; 9C9AADA98B24B035 CRC64;
MNHKSKKRIR EAKRSARPEL KDSLDWTRHN YYESFSLSPA AVADNVERAD ALQLSVEEFV
ERYERPYKPV VLLNAQEGWS AQEKWTLERL KRKYRNQKFK CGEDNDGYSV KMKMKYYIEY
MESTRDDSPL YIFDSSYGEH PKRRKLLEDY KVPKFFTDDL FQYAGEKRRP PYRWFVMGPP
RSGTGIHIDP LGTSAWNALV QGHKRWCLFP TSTPRELIKV TRDEGGNQQD EAITWFNVIY
PRTQLPTWPP EFKPLEILQK PGETVFVPGG WWHVVLNLDT TIAITQNFAS STNFPVVWHK
TVRGRPKLSR KWYRILKQEH PELAVLADSV DLQESTGIAS DSSSDSSSSS SSSSSDSDSE
CESGSEGDGT VHRRKKRRTC SMVGNGDTTS QDDCVSKERS SSR
