ID   ZN746_HUMAN             Reviewed;         644 AA.
AC   Q6NUN9; A8K6Z9; Q6ZRF9;
DT   17-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT   05-JUL-2004, sequence version 1.
DT   27-MAR-2024, entry version 160.
DE   RecName: Full=Zinc finger protein 746 {ECO:0000305};
DE   AltName: Full=Parkin-interacting substrate;
DE            Short=PARIS;
GN   Name=ZNF746 {ECO:0000312|HGNC:HGNC:21948}; Synonyms=PARIS;
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 [LARGE SCALE MRNA] (ISOFORMS 2 AND 3).
RC   TISSUE=Prostate, and Testis;
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   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=12853948; DOI=10.1038/nature01782;
RA   Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA   Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K.,
RA   Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A.,
RA   Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H.,
RA   Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A.,
RA   Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P.,
RA   Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M.,
RA   Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S.,
RA   Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R.,
RA   Strowmatt C., Latreille P., Miller N., Johnson D., Murray J.,
RA   Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W.,
RA   Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E.,
RA   Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A.,
RA   Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA   Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E.,
RA   Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A.,
RA   Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A.,
RA   Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R.,
RA   McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H.,
RA   Wilson R.K.;
RT   "The DNA sequence of human chromosome 7.";
RL   Nature 424:157-164(2003).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Placenta;
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   [4]
RP   FUNCTION, SUBCELLULAR LOCATION, UBIQUITINATION, AND MUTAGENESIS OF CYS-458;
RP   HIS-471; CYS-518; HIS-528; CYS-543; HIS-560; CYS-571 AND HIS-584.
RX   PubMed=21376232; DOI=10.1016/j.cell.2011.02.010;
RA   Shin J.H., Ko H.S., Kang H., Lee Y., Lee Y.I., Pletinkova O.,
RA   Troconso J.C., Dawson V.L., Dawson T.M.;
RT   "PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration
RT   in Parkinson's disease.";
RL   Cell 144:689-702(2011).
RN   [5]
RP   SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-282 AND LYS-286, 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   [6]
RP   FUNCTION, SUBUNIT, AND INTERACTION WITH TRIM28.
RX   PubMed=31856708; DOI=10.1186/s12860-019-0243-y;
RA   Al Chiblak M., Steinbeck F., Thiesen H.J., Lorenz P.;
RT   "DUF3669, a 'domain of unknown function' within ZNF746 and ZNF777,
RT   oligomerizes and contributes to transcriptional repression.";
RL   BMC Mol. Cell Biol. 20:60-60(2019).
CC   -!- FUNCTION: Transcription repressor that specifically binds to the 5'-
CC       TATTTT[T/G]-3' consensus sequence on promoters and repress
CC       transcription of PGC-1-alpha (PPARGC1A), thereby playing a role in
CC       regulation of neuron death. {ECO:0000269|PubMed:21376232,
CC       ECO:0000269|PubMed:31856708}.
CC   -!- SUBUNIT: Homooligomer, heterooligomer with ZNF746 (PubMed:31856708).
CC       Interacts (via C2H2-type zinc fingers) with PRKN (By similarity).
CC       {ECO:0000250|UniProtKB:Q3U133, ECO:0000269|PubMed:31856708}.
CC   -!- SUBUNIT: [Isoform 1]: Interacts with TRIM28.
CC       {ECO:0000269|PubMed:31856708}.
CC   -!- INTERACTION:
CC       Q6NUN9; O60260: PRKN; NbExp=6; IntAct=EBI-3862525, EBI-716346;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21376232}. Nucleus
CC       {ECO:0000305|PubMed:21376232}. Note=Mainly localizes to the cytoplasm;
CC       probably translocates to the nucleus to repress selected genes.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=3;
CC       Name=1;
CC         IsoId=Q6NUN9-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q6NUN9-2; Sequence=VSP_041053;
CC       Name=3;
CC         IsoId=Q6NUN9-3; Sequence=VSP_041052;
CC   -!- PTM: Ubiquitinated by PRKN. 'Lys-48'-linked polyubiquitination by PRKN
CC       leads to degradation by the proteasome and may play a key role in
CC       regulation of neuron death. {ECO:0000269|PubMed:21376232}.
CC   -!- MISCELLANEOUS: May act as a downstream effector of PRKN and contribute
CC       to neurodegeneration in Parkinson disease cases caused by defects in
CC       PRKN: its accumulation due to the absence of PRKN, followed by up-
CC       regulation of PPARGC1A, could lead to the selective loss of dopamine
CC       neurons in the substantia nigra. {ECO:0000305|PubMed:21376232}.
CC   -!- SIMILARITY: Belongs to the krueppel C2H2-type zinc-finger protein
CC       family. {ECO:0000305}.
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DR   EMBL; AK128244; BAC87351.1; -; mRNA.
DR   EMBL; AK291814; BAF84503.1; -; mRNA.
DR   EMBL; AC073314; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC068505; AAH68505.1; -; mRNA.
DR   CCDS; CCDS55180.1; -. [Q6NUN9-2]
DR   CCDS; CCDS5897.1; -. [Q6NUN9-1]
DR   RefSeq; NP_001156946.1; NM_001163474.1. [Q6NUN9-2]
DR   RefSeq; NP_689770.3; NM_152557.4. [Q6NUN9-1]
DR   AlphaFoldDB; Q6NUN9; -.
DR   SMR; Q6NUN9; -.
DR   BioGRID; 127574; 320.
DR   IntAct; Q6NUN9; 36.
DR   MINT; Q6NUN9; -.
DR   STRING; 9606.ENSP00000493970; -.
DR   iPTMnet; Q6NUN9; -.
DR   PhosphoSitePlus; Q6NUN9; -.
DR   BioMuta; ZNF746; -.
DR   DMDM; 74736828; -.
DR   EPD; Q6NUN9; -.
DR   jPOST; Q6NUN9; -.
DR   MassIVE; Q6NUN9; -.
DR   MaxQB; Q6NUN9; -.
DR   PaxDb; 9606-ENSP00000395007; -.
DR   PeptideAtlas; Q6NUN9; -.
DR   ProteomicsDB; 66696; -. [Q6NUN9-1]
DR   ProteomicsDB; 66697; -. [Q6NUN9-2]
DR   ProteomicsDB; 66698; -. [Q6NUN9-3]
DR   Pumba; Q6NUN9; -.
DR   ABCD; Q6NUN9; 1 sequenced antibody.
DR   Antibodypedia; 46329; 74 antibodies from 21 providers.
DR   DNASU; 155061; -.
DR   Ensembl; ENST00000340622.8; ENSP00000345140.3; ENSG00000181220.18. [Q6NUN9-1]
DR   Ensembl; ENST00000685153.1; ENSP00000508891.1; ENSG00000181220.18. [Q6NUN9-2]
DR   GeneID; 155061; -.
DR   KEGG; hsa:155061; -.
DR   UCSC; uc003wfw.3; human. [Q6NUN9-1]
DR   AGR; HGNC:21948; -.
DR   CTD; 155061; -.
DR   DisGeNET; 155061; -.
DR   GeneCards; ZNF746; -.
DR   HGNC; HGNC:21948; ZNF746.
DR   HPA; ENSG00000181220; Low tissue specificity.
DR   MIM; 613914; gene.
DR   neXtProt; NX_Q6NUN9; -.
DR   OpenTargets; ENSG00000181220; -.
DR   PharmGKB; PA144596520; -.
DR   VEuPathDB; HostDB:ENSG00000181220; -.
DR   eggNOG; KOG1721; Eukaryota.
DR   GeneTree; ENSGT00940000161747; -.
DR   HOGENOM; CLU_002678_76_3_1; -.
DR   InParanoid; Q6NUN9; -.
DR   OrthoDB; 4614113at2759; -.
DR   PhylomeDB; Q6NUN9; -.
DR   TreeFam; TF337777; -.
DR   PathwayCommons; Q6NUN9; -.
DR   Reactome; R-HSA-212436; Generic Transcription Pathway.
DR   SignaLink; Q6NUN9; -.
DR   SIGNOR; Q6NUN9; -.
DR   BioGRID-ORCS; 155061; 7 hits in 1175 CRISPR screens.
DR   ChiTaRS; ZNF746; human.
DR   GenomeRNAi; 155061; -.
DR   Pharos; Q6NUN9; Tbio.
DR   PRO; PR:Q6NUN9; -.
DR   Proteomes; UP000005640; Chromosome 7.
DR   RNAct; Q6NUN9; Protein.
DR   Bgee; ENSG00000181220; Expressed in blood and 164 other cell types or tissues.
DR   ExpressionAtlas; Q6NUN9; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005829; C:cytosol; IDA:HPA.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0005634; C:nucleus; IC:ParkinsonsUK-UCL.
DR   GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:ParkinsonsUK-UCL.
DR   GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IDA:NTNU_SB.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:NTNU_SB.
DR   GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:UniProtKB.
DR   GO; GO:0045892; P:negative regulation of DNA-templated transcription; IDA:UniProtKB.
DR   GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:ParkinsonsUK-UCL.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:ParkinsonsUK-UCL.
DR   GO; GO:0051291; P:protein heterooligomerization; IDA:UniProtKB.
DR   GO; GO:0051260; P:protein homooligomerization; IDA:UniProtKB.
DR   CDD; cd07765; KRAB_A-box; 1.
DR   Gene3D; 6.10.140.140; -; 1.
DR   Gene3D; 3.30.160.60; Classic Zinc Finger; 4.
DR   InterPro; IPR001909; KRAB.
DR   InterPro; IPR036051; KRAB_dom_sf.
DR   InterPro; IPR036236; Znf_C2H2_sf.
DR   InterPro; IPR013087; Znf_C2H2_type.
DR   PANTHER; PTHR23232; KRAB DOMAIN C2H2 ZINC FINGER; 1.
DR   PANTHER; PTHR23232:SF145; ZINC FINGER PROTEIN 746-RELATED; 1.
DR   Pfam; PF01352; KRAB; 1.
DR   Pfam; PF00096; zf-C2H2; 4.
DR   SMART; SM00349; KRAB; 1.
DR   SMART; SM00355; ZnF_C2H2; 4.
DR   SUPFAM; SSF57667; beta-beta-alpha zinc fingers; 3.
DR   SUPFAM; SSF109640; KRAB domain (Kruppel-associated box); 1.
DR   PROSITE; PS50805; KRAB; 1.
DR   PROSITE; PS00028; ZINC_FINGER_C2H2_1; 3.
DR   PROSITE; PS50157; ZINC_FINGER_C2H2_2; 4.
DR   Genevisible; Q6NUN9; HS.
PE   1: Evidence at protein level;
KW   Alternative splicing; Coiled coil; Cytoplasm; DNA-binding; Isopeptide bond;
KW   Metal-binding; Nucleus; Reference proteome; Repeat; Repressor;
KW   Transcription; Transcription regulation; Ubl conjugation; Zinc;
KW   Zinc-finger.
FT   CHAIN           1..644
FT                   /note="Zinc finger protein 746"
FT                   /id="PRO_0000253728"
FT   DOMAIN          96..167
FT                   /note="KRAB"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00119"
FT   ZN_FING         453..478
FT                   /note="C2H2-type 1; degenerate"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00042"
FT   ZN_FING         510..532
FT                   /note="C2H2-type 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00042"
FT   ZN_FING         538..560
FT                   /note="C2H2-type 3"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00042"
FT   ZN_FING         566..588
FT                   /note="C2H2-type 4"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00042"
FT   REGION          153..176
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          324..370
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          472..503
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          581..623
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COILED          16..92
FT                   /evidence="ECO:0000255"
FT   COMPBIAS        598..614
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   CROSSLNK        282
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in SUMO2)"
FT                   /evidence="ECO:0007744|PubMed:28112733"
FT   CROSSLNK        286
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in SUMO2)"
FT                   /evidence="ECO:0007744|PubMed:28112733"
FT   VAR_SEQ         1..185
FT                   /note="Missing (in isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_041052"
FT   VAR_SEQ         279
FT                   /note="E -> EA (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:14702039"
FT                   /id="VSP_041053"
FT   MUTAGEN         458
FT                   /note="C->A: No effect."
FT                   /evidence="ECO:0000269|PubMed:21376232"
FT   MUTAGEN         471
FT                   /note="H->A: No effect."
FT                   /evidence="ECO:0000269|PubMed:21376232"
FT   MUTAGEN         518
FT                   /note="C->A: No effect."
FT                   /evidence="ECO:0000269|PubMed:21376232"
FT   MUTAGEN         528
FT                   /note="H->A: No effect."
FT                   /evidence="ECO:0000269|PubMed:21376232"
FT   MUTAGEN         543
FT                   /note="C->A: No effect."
FT                   /evidence="ECO:0000269|PubMed:21376232"
FT   MUTAGEN         560
FT                   /note="H->A: No effect."
FT                   /evidence="ECO:0000269|PubMed:21376232"
FT   MUTAGEN         571
FT                   /note="C->A: Impairs DNA-binding and ability to repress
FT                   PGC-1-alpha (PPARGC1A)."
FT                   /evidence="ECO:0000269|PubMed:21376232"
FT   MUTAGEN         584
FT                   /note="H->A: No effect."
FT                   /evidence="ECO:0000269|PubMed:21376232"
SQ   SEQUENCE   644 AA;  69136 MW;  4F6723D2225D95AB CRC64;
     MAEAVAAPIS PWTMAATIQA MERKIESQAA RLLSLEGRTG MAEKKLADCE KTAVEFGNQL
     EGKWAVLGTL LQEYGLLQRR LENVENLLRN RNFWILRLPP GSKGESPKEW GKLEDWQKEL
     YKHVMRGNYE TLVSLDYAIS KPEVLSQIEQ GKEPCNWRRP GPKIPDVPVD PSPGSGPPVP
     APDLLMQIKQ EGELQLQEQQ ALGVEAWAAG QPDIGEEPWG LSQLDSGAGD ISTDATSGVH
     SNFSTTIPPT SWQTDLPPHH PSSACSDGTL KLNTAASTED VKIVIKTEVQ EEEVVATPVH
     PTDLEAHGTL FGPGQATRFF PSPAQEGAWE SQGSSFPSQD PVLGLREPAR PERDMGELSP
     AVAQEETPPG DWLFGGVRWG WNFRCKPPVG LNPRTGPEGL PYSSPDNGEA ILDPSQAPRP
     FNEPCKYPGR TKGFGHKPGL KKHPAAPPGG RPFTCATCGK SFQLQVSLSA HQRSCGAPDG
     SGPGTGGGGS GSGGGGGGSG GGSARDGSAL RCGECGRCFT RPAHLIRHRM LHTGERPFPC
     TECEKRFTER SKLIDHYRTH TGVRPFTCTV CGKSFIRKDH LRKHQRNHAA GAKTPARGQP
     LPTPPAPPDP FKSPASKGPL ASTDLVTDWT CGLSVLGPTD GGDM
//