ZHX2_HUMAN
ID ZHX2_HUMAN Reviewed; 837 AA.
AC Q9Y6X8;
DT 01-MAR-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 03-AUG-2022, entry version 184.
DE RecName: Full=Zinc fingers and homeoboxes protein 2;
DE AltName: Full=Alpha-fetoprotein regulator 1;
DE Short=AFP regulator 1;
DE AltName: Full=Regulator of AFP;
DE AltName: Full=Zinc finger and homeodomain protein 2;
GN Name=ZHX2; Synonyms=AFR1, KIAA0854, RAF;
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:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBUNIT, INTERACTION WITH NFYA,
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RC TISSUE=Testis {ECO:0000312|EMBL:BAC76615.1};
RX PubMed=12741956; DOI=10.1042/bj20030171;
RA Kawata H., Yamada K., Shou Z., Mizutani T., Yazawa T., Yoshino M.,
RA Sekiguchi T., Kajitani T., Miyamoto K.;
RT "Zinc-fingers and homeoboxes (ZHX) 2, a novel member of the ZHX family,
RT functions as a transcriptional repressor.";
RL Biochem. J. 373:747-757(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=10048485; DOI=10.1093/dnares/5.6.355;
RA Nagase T., Ishikawa K., Suyama M., Kikuno R., Hirosawa M., Miyajima N.,
RA Tanaka A., Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XII. The
RT complete sequences of 100 new cDNA clones from brain which code for large
RT proteins in vitro.";
RL DNA Res. 5:355-364(1998).
RN [3]
RP SEQUENCE REVISION.
RA Ohara O., Suyama M., Kikuno R., Nagase T., Ishikawa K.;
RL Submitted (JAN-2004) to the EMBL/GenBank/DDBJ databases.
RN [4] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lymph {ECO:0000312|EMBL:AAH42145.1};
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 [5]
RP SUBUNIT.
RX PubMed=14659886; DOI=10.1016/j.gene.2003.09.013;
RA Kawata H., Yamada K., Shou Z., Mizutani T., Miyamoto K.;
RT "The mouse zinc-fingers and homeoboxes (ZHX) family: ZHX2 forms a
RT heterodimer with ZHX3.";
RL Gene 323:133-140(2003).
RN [6]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RC TISSUE=Kidney;
RX PubMed=17056598; DOI=10.1074/jbc.m606664200;
RA Liu G., Clement L.C., Kanwar Y.S., Avila-Casado C., Chugh S.S.;
RT "ZHX proteins regulate podocyte gene expression during the development of
RT nephrotic syndrome.";
RL J. Biol. Chem. 281:39681-39692(2006).
RN [7]
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 [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-37 AND THR-207, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
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 [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-37, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [10]
RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-64 AND LYS-455, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=28112733; DOI=10.1038/nsmb.3366;
RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C.,
RA Nielsen M.L.;
RT "Site-specific mapping of the human SUMO proteome reveals co-modification
RT with phosphorylation.";
RL Nat. Struct. Mol. Biol. 24:325-336(2017).
RN [11]
RP STRUCTURE BY NMR OF 524-601.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the third homeobox domain of zinc fingers and
RT homeoboxes protein 2.";
RL Submitted (OCT-2006) to the PDB data bank.
RN [12]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 444-501.
RX PubMed=20509910; DOI=10.1186/1472-6807-10-13;
RA Bird L.E., Ren J., Nettleship J.E., Folkers G.E., Owens R.J.,
RA Stammers D.K.;
RT "Novel structural features in two ZHX homeodomains derived from a
RT systematic study of single and multiple domains.";
RL BMC Struct. Biol. 10:13-13(2010).
CC -!- FUNCTION: Acts as a transcriptional repressor (PubMed:12741956).
CC Represses the promoter activity of the CDC25C gene stimulated by NFYA
CC (PubMed:12741956). May play a role in retinal development where it
CC regulates the composition of bipolar cell populations, by promoting
CC differentiation of bipolar OFF-type cells (By similarity). In the
CC brain, may promote maintenance and suppress differentiation of neural
CC progenitor cells in the developing cortex (By similarity).
CC {ECO:0000250|UniProtKB:Q8C0C0, ECO:0000269|PubMed:12741956}.
CC -!- SUBUNIT: Homodimer (via homeobox domain) (PubMed:12741956,
CC PubMed:14659886). Heterodimer with ZHX1 (via homeobox domain 1)
CC (PubMed:12741956). Heterodimer with ZHX3 (via homeobox domain 1)
CC (PubMed:12741956, PubMed:14659886). Heterodimerization with ZHX1 is not
CC necessary for repressor activity (PubMed:12741956). Interacts (via
CC homeobox domain) with NFYA (via N-terminus) (PubMed:12741956).
CC Interacts with EFNB1 intracellular domain peptide; the interaction
CC enhances ZHX2 transcriptional repression activity (By similarity).
CC {ECO:0000250|UniProtKB:Q8C0C0, ECO:0000269|PubMed:12741956,
CC ECO:0000269|PubMed:14659886}.
CC -!- INTERACTION:
CC Q9Y6X8; Q03403: TFF2; NbExp=3; IntAct=EBI-948566, EBI-4314702;
CC Q9Y6X8; Q9UKY1: ZHX1; NbExp=2; IntAct=EBI-948566, EBI-347767;
CC Q9Y6X8; Q9Y6X8: ZHX2; NbExp=2; IntAct=EBI-948566, EBI-948566;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00108,
CC ECO:0000269|PubMed:12741956, ECO:0000269|PubMed:17056598}.
CC Note=Colocalizes with EFNB1 intracellular domain in the nucleus.
CC {ECO:0000250|UniProtKB:Q8C0C0}.
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. Expressed in podocytes.
CC {ECO:0000269|PubMed:12741956, ECO:0000269|PubMed:17056598}.
CC -!- SIMILARITY: Belongs to the ZHX family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA74877.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AB083653; BAC76615.1; -; mRNA.
DR EMBL; AB020661; BAA74877.2; ALT_INIT; mRNA.
DR EMBL; BC042145; AAH42145.1; -; mRNA.
DR CCDS; CCDS6336.1; -.
DR RefSeq; NP_055758.1; NM_014943.3.
DR RefSeq; XP_005250893.1; XM_005250836.4.
DR RefSeq; XP_005250894.1; XM_005250837.4.
DR RefSeq; XP_011515233.1; XM_011516931.2.
DR RefSeq; XP_011515234.1; XM_011516932.2.
DR PDB; 2DMP; NMR; -; A=524-599.
DR PDB; 3NAU; X-ray; 2.70 A; A/B=444-501.
DR PDBsum; 2DMP; -.
DR PDBsum; 3NAU; -.
DR AlphaFoldDB; Q9Y6X8; -.
DR SMR; Q9Y6X8; -.
DR BioGRID; 116549; 50.
DR IntAct; Q9Y6X8; 61.
DR MINT; Q9Y6X8; -.
DR STRING; 9606.ENSP00000314709; -.
DR GlyGen; Q9Y6X8; 2 sites, 2 O-linked glycans (2 sites).
DR iPTMnet; Q9Y6X8; -.
DR PhosphoSitePlus; Q9Y6X8; -.
DR BioMuta; ZHX2; -.
DR DMDM; 44888553; -.
DR EPD; Q9Y6X8; -.
DR jPOST; Q9Y6X8; -.
DR MassIVE; Q9Y6X8; -.
DR MaxQB; Q9Y6X8; -.
DR PaxDb; Q9Y6X8; -.
DR PeptideAtlas; Q9Y6X8; -.
DR PRIDE; Q9Y6X8; -.
DR ProteomicsDB; 86821; -.
DR Antibodypedia; 13770; 386 antibodies from 35 providers.
DR DNASU; 22882; -.
DR Ensembl; ENST00000314393.6; ENSP00000314709.4; ENSG00000178764.8.
DR GeneID; 22882; -.
DR KEGG; hsa:22882; -.
DR MANE-Select; ENST00000314393.6; ENSP00000314709.4; NM_014943.5; NP_055758.1.
DR UCSC; uc003ypk.2; human.
DR CTD; 22882; -.
DR DisGeNET; 22882; -.
DR GeneCards; ZHX2; -.
DR HGNC; HGNC:18513; ZHX2.
DR HPA; ENSG00000178764; Low tissue specificity.
DR MIM; 609185; gene.
DR neXtProt; NX_Q9Y6X8; -.
DR OpenTargets; ENSG00000178764; -.
DR PharmGKB; PA128394591; -.
DR VEuPathDB; HostDB:ENSG00000178764; -.
DR eggNOG; ENOG502RHIC; Eukaryota.
DR GeneTree; ENSGT00950000182893; -.
DR HOGENOM; CLU_009147_1_0_1; -.
DR InParanoid; Q9Y6X8; -.
DR OMA; AKDQMAI; -.
DR OrthoDB; 518562at2759; -.
DR PhylomeDB; Q9Y6X8; -.
DR TreeFam; TF333363; -.
DR PathwayCommons; Q9Y6X8; -.
DR SignaLink; Q9Y6X8; -.
DR BioGRID-ORCS; 22882; 10 hits in 1094 CRISPR screens.
DR ChiTaRS; ZHX2; human.
DR EvolutionaryTrace; Q9Y6X8; -.
DR GeneWiki; ZHX2; -.
DR GenomeRNAi; 22882; -.
DR Pharos; Q9Y6X8; Tbio.
DR PRO; PR:Q9Y6X8; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; Q9Y6X8; protein.
DR Bgee; ENSG00000178764; Expressed in superficial temporal artery and 204 other tissues.
DR ExpressionAtlas; Q9Y6X8; baseline and differential.
DR Genevisible; Q9Y6X8; HS.
DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0046982; F:protein heterodimerization activity; IDA:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0006402; P:mRNA catabolic process; IEA:Ensembl.
DR GO; GO:0045665; P:negative regulation of neuron differentiation; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0060040; P:retinal bipolar neuron differentiation; IEA:Ensembl.
DR GO; GO:0035019; P:somatic stem cell population maintenance; IEA:Ensembl.
DR CDD; cd00086; homeodomain; 4.
DR InterPro; IPR009057; Homeobox-like_sf.
DR InterPro; IPR001356; Homeobox_dom.
DR InterPro; IPR041057; ZHX_Znf_C2H2.
DR InterPro; IPR036236; Znf_C2H2_sf.
DR InterPro; IPR013087; Znf_C2H2_type.
DR Pfam; PF00046; Homeodomain; 3.
DR Pfam; PF18387; zf_C2H2_ZHX; 1.
DR SMART; SM00389; HOX; 4.
DR SMART; SM00355; ZnF_C2H2; 2.
DR SUPFAM; SSF46689; SSF46689; 4.
DR SUPFAM; SSF57667; SSF57667; 2.
DR PROSITE; PS50071; HOMEOBOX_2; 3.
DR PROSITE; PS50157; ZINC_FINGER_C2H2_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Differentiation; DNA-binding; Homeobox; Isopeptide bond;
KW Metal-binding; Neurogenesis; Nucleus; Phosphoprotein; Reference proteome;
KW Repeat; Repressor; Transcription; Transcription regulation;
KW Ubl conjugation; Zinc; Zinc-finger.
FT CHAIN 1..837
FT /note="Zinc fingers and homeoboxes protein 2"
FT /id="PRO_0000049391"
FT ZN_FING 78..101
FT /note="C2H2-type 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042,
FT ECO:0000305"
FT ZN_FING 110..133
FT /note="C2H2-type 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00042,
FT ECO:0000305"
FT DNA_BIND 263..324
FT /note="Homeobox 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00108,
FT ECO:0000305"
FT DNA_BIND 439..501
FT /note="Homeobox 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00108,
FT ECO:0000305"
FT DNA_BIND 530..591
FT /note="Homeobox 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00108,
FT ECO:0000305"
FT DNA_BIND 628..690
FT /note="Homeobox 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00108,
FT ECO:0000305"
FT REGION 27..77
FT /note="Interaction with EFNB1"
FT /evidence="ECO:0000250|UniProtKB:Q8C0C0"
FT REGION 164..204
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 195..358
FT /note="Required for homodimerization"
FT /evidence="ECO:0000269|PubMed:12741956"
FT REGION 263..497
FT /note="Required for interaction with NFYA"
FT /evidence="ECO:0000269|PubMed:12741956"
FT REGION 263..446
FT /note="Required for repressor activity"
FT /evidence="ECO:0000269|PubMed:12741956"
FT REGION 317..446
FT /note="Required for nuclear localization"
FT /evidence="ECO:0000269|PubMed:12741956"
FT REGION 404..445
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 755..837
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 164..182
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 190..204
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 422..437
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 770..784
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 37
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:23186163,
FT ECO:0007744|PubMed:24275569"
FT MOD_RES 207
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 825
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8C0C0"
FT MOD_RES 827
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8C0C0"
FT CROSSLNK 64
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:28112733"
FT CROSSLNK 455
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:28112733"
FT VARIANT 357
FT /note="V -> M (in dbSNP:rs9649951)"
FT /id="VAR_049594"
FT VARIANT 649
FT /note="R -> K (in dbSNP:rs35319449)"
FT /id="VAR_049595"
FT VARIANT 779
FT /note="G -> S (in dbSNP:rs3802264)"
FT /id="VAR_049596"
FT HELIX 448..459
FT /evidence="ECO:0007829|PDB:3NAU"
FT HELIX 460..462
FT /evidence="ECO:0007829|PDB:3NAU"
FT HELIX 466..476
FT /evidence="ECO:0007829|PDB:3NAU"
FT HELIX 480..500
FT /evidence="ECO:0007829|PDB:3NAU"
FT HELIX 538..550
FT /evidence="ECO:0007829|PDB:2DMP"
FT HELIX 556..566
FT /evidence="ECO:0007829|PDB:2DMP"
FT HELIX 570..585
FT /evidence="ECO:0007829|PDB:2DMP"
SQ SEQUENCE 837 AA; 92307 MW; BE377ADF76D987D2 CRC64;
MASKRKSTTP CMVRTSQVVE QDVPEEVDRA KEKGIGTPQP DVAKDSWAAE LENSSKENEV
IEVKSMGESQ SKKLQGGYEC KYCPYSTQNL NEFTEHVDMQ HPNVILNPLY VCAECNFTTK
KYDSLSDHNS KFHPGEANFK LKLIKRNNQT VLEQSIETTN HVVSITTSGP GTGDSDSGIS
VSKTPIMKPG KPKADAKKVP KKPEEITPEN HVEGTARLVT DTAEILSRLG GVELLQDTLG
HVMPSVQLPP NINLVPKVPV PLNTTKYNSA LDTNATMINS FNKFPYPTQA ELSWLTAASK
HPEEHIRIWF ATQRLKHGIS WSPEEVEEAR KKMFNGTIQS VPPTITVLPA QLAPTKVTQP
ILQTALPCQI LGQTSLVLTQ VTSGSTTVSC SPITLAVAGV TNHGQKRPLV TPQAAPEPKR
PHIAQVPEPP PKVANPPLTP ASDRKKTKEQ IAHLKASFLQ SQFPDDAEVY RLIEVTGLAR
SEIKKWFSDH RYRCQRGIVH ITSESLAKDQ LAIAASRHGR TYHAYPDFAP QKFKEKTQGQ
VKILEDSFLK SSFPTQAELD RLRVETKLSR REIDSWFSER RKLRDSMEQA VLDSMGSGKK
GQDVGAPNGA LSRLDQLSGA QLTSSLPSPS PAIAKSQEQV HLLRSTFART QWPTPQEYDQ
LAAKTGLVRT EIVRWFKENR CLLKTGTVKW MEQYQHQPMA DDHGYDAVAR KATKPMAESP
KNGGDVVPQY YKDPKKLCEE DLEKLVTRVK VGSEPAKDCL PAKPSEATSD RSEGSSRDGQ
GSDENEESSV VDYVEVTVGE EDAISDRSDS WSQAAAEGVS ELAESDSDCV PAEAGQA
