ID HES6_HUMAN Reviewed; 224 AA. AC Q96HZ4; A8KAP6; B8ZZA9; Q53SN9; Q8N2J2; Q96T93; Q9P2S3; DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2001, sequence version 1. DT 24-JAN-2024, entry version 174. DE RecName: Full=Transcription cofactor HES-6; DE AltName: Full=C-HAIRY1; DE AltName: Full=Class B basic helix-loop-helix protein 41; DE Short=bHLHb41; DE AltName: Full=Hairy and enhancer of split 6; GN Name=HES6 {ECO:0000312|EMBL:AAK51634.1}; Synonyms=BHLHB41; 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:BAA96082.1} RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3). RX PubMed=10851137; DOI=10.1242/dev.127.13.2933; RA Bae S.-K., Bessho Y., Hojo M., Kageyama R.; RT "The bHLH gene Hes6, an inhibitor of Hes1, promotes neuronal RT differentiation."; RL Development 127:2933-2943(2000). RN [2] {ECO:0000312|EMBL:AAK51634.1} RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=11044617; DOI=10.1016/s0925-4773(00)00443-3; RA Vasiliauskas D., Stern C.D.; RT "Expression of mouse HES-6, a new member of the Hairy/Enhancer of split RT family of bHLH transcription factors."; RL Mech. Dev. 98:133-137(2000). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Ovary; 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=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). 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] {ECO:0000312|EMBL:AAH07939.1} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Muscle {ECO:0000312|EMBL:AAH07939.1}; 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). CC -!- FUNCTION: Does not bind DNA itself but suppresses both HES1-mediated N CC box-dependent transcriptional repression and binding of HES1 to E box CC sequences. Also suppresses HES1-mediated inhibition of the heterodimer CC formed by ASCL1/MASH1 and TCF3/E47, allowing ASCL1 and TCF3 to up- CC regulate transcription in its presence. Promotes cell differentiation CC (By similarity). {ECO:0000250}. CC -!- SUBUNIT: Transcription repression requires formation of a complex with CC a corepressor protein of the Groucho/TLE family. Interacts with HES1 CC (By similarity). {ECO:0000250}. CC -!- INTERACTION: CC Q96HZ4; Q9NWQ9: C14orf119; NbExp=3; IntAct=EBI-7469266, EBI-725606; CC Q96HZ4; P60411: KRTAP10-9; NbExp=3; IntAct=EBI-7469266, EBI-10172052; CC Q96HZ4; P61019: RAB2A; NbExp=3; IntAct=EBI-7469266, EBI-752037; CC Q96HZ4; Q96GM5: SMARCD1; NbExp=3; IntAct=EBI-7469266, EBI-358489; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000305}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; CC IsoId=Q96HZ4-1; Sequence=Displayed; CC Name=2; CC IsoId=Q96HZ4-2; Sequence=VSP_011152; CC Name=3; CC IsoId=Q96HZ4-3; Sequence=VSP_040128; CC Name=4; CC IsoId=Q96HZ4-4; Sequence=VSP_055615, VSP_055616; CC -!- DOMAIN: The C-terminal WRPW motif is a transcriptional repression CC domain necessary for the interaction with Groucho/TLE family members, CC transcriptional corepressors recruited to specific target DNA by Hairy- CC related proteins. {ECO:0000250}. CC -!- DOMAIN: Has a particular type of basic domain (presence of a helix- CC interrupting proline) that binds to the N-box (CACNAG), rather than the CC canonical E-box (CANNTG). CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AB035179; BAA96082.1; -; mRNA. DR EMBL; AF260237; AAK51634.1; -; mRNA. DR EMBL; AK075040; BAC11368.1; -; mRNA. DR EMBL; AK293111; BAF85800.1; -; mRNA. DR EMBL; AC016757; AAY24337.1; -; Genomic_DNA. DR EMBL; CH471063; EAW71151.1; -; Genomic_DNA. DR EMBL; BC007939; AAH07939.1; -; mRNA. DR CCDS; CCDS2527.1; -. [Q96HZ4-1] DR CCDS; CCDS46556.1; -. [Q96HZ4-3] DR CCDS; CCDS63180.1; -. [Q96HZ4-4] DR RefSeq; NP_001136325.1; NM_001142853.2. [Q96HZ4-3] DR RefSeq; NP_001269363.1; NM_001282434.1. [Q96HZ4-4] DR RefSeq; NP_061115.2; NM_018645.5. [Q96HZ4-1] DR AlphaFoldDB; Q96HZ4; -. DR SMR; Q96HZ4; -. DR BioGRID; 120682; 52. DR ELM; Q96HZ4; -. DR IntAct; Q96HZ4; 7. DR MINT; Q96HZ4; -. DR STRING; 9606.ENSP00000272937; -. DR iPTMnet; Q96HZ4; -. DR PhosphoSitePlus; Q96HZ4; -. DR BioMuta; HES6; -. DR DMDM; 50400609; -. DR MassIVE; Q96HZ4; -. DR PaxDb; 9606-ENSP00000272937; -. DR PeptideAtlas; Q96HZ4; -. DR ProteomicsDB; 7344; -. DR ProteomicsDB; 76797; -. [Q96HZ4-1] DR ProteomicsDB; 76798; -. [Q96HZ4-2] DR ProteomicsDB; 76799; -. [Q96HZ4-3] DR Antibodypedia; 20277; 340 antibodies from 31 providers. DR DNASU; 55502; -. DR Ensembl; ENST00000272937.10; ENSP00000272937.5; ENSG00000144485.11. [Q96HZ4-1] DR Ensembl; ENST00000409002.7; ENSP00000387155.3; ENSG00000144485.11. [Q96HZ4-3] DR Ensembl; ENST00000409160.7; ENSP00000387215.3; ENSG00000144485.11. [Q96HZ4-2] DR Ensembl; ENST00000409574.1; ENSP00000387008.1; ENSG00000144485.11. [Q96HZ4-4] DR GeneID; 55502; -. DR KEGG; hsa:55502; -. DR MANE-Select; ENST00000272937.10; ENSP00000272937.5; NM_018645.6; NP_061115.2. DR UCSC; uc002vxz.4; human. [Q96HZ4-1] DR AGR; HGNC:18254; -. DR CTD; 55502; -. DR DisGeNET; 55502; -. DR GeneCards; HES6; -. DR HGNC; HGNC:18254; HES6. DR HPA; ENSG00000144485; Tissue enhanced (brain, pituitary gland). DR MIM; 610331; gene. DR neXtProt; NX_Q96HZ4; -. DR OpenTargets; ENSG00000144485; -. DR PharmGKB; PA29253; -. DR VEuPathDB; HostDB:ENSG00000144485; -. DR eggNOG; KOG4304; Eukaryota. DR GeneTree; ENSGT00940000161398; -. DR HOGENOM; CLU_068550_0_0_1; -. DR InParanoid; Q96HZ4; -. DR OMA; EDESCYG; -. DR OrthoDB; 3679915at2759; -. DR PhylomeDB; Q96HZ4; -. DR TreeFam; TF351373; -. DR PathwayCommons; Q96HZ4; -. DR SignaLink; Q96HZ4; -. DR SIGNOR; Q96HZ4; -. DR BioGRID-ORCS; 55502; 19 hits in 1176 CRISPR screens. DR ChiTaRS; HES6; human. DR GeneWiki; HES6; -. DR GenomeRNAi; 55502; -. DR Pharos; Q96HZ4; Tbio. DR PRO; PR:Q96HZ4; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; Q96HZ4; Protein. DR Bgee; ENSG00000144485; Expressed in ganglionic eminence and 121 other cell types or tissues. DR ExpressionAtlas; Q96HZ4; baseline and differential. DR Genevisible; Q96HZ4; HS. DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB. DR GO; GO:0005634; C:nucleus; IBA:GO_Central. DR GO; GO:0005667; C:transcription regulator complex; ISS:UniProtKB. DR GO; GO:0003700; F:DNA-binding transcription factor activity; TAS:ProtInc. DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB. DR GO; GO:0001227; F:DNA-binding transcription repressor activity, RNA polymerase II-specific; IEA:Ensembl. DR GO; GO:0046983; F:protein dimerization activity; IEA:InterPro. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central. DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; ISS:ARUK-UCL. DR GO; GO:1990837; F:sequence-specific double-stranded DNA binding; IDA:ARUK-UCL. DR GO; GO:0009952; P:anterior/posterior pattern specification; IBA:GO_Central. DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW. DR GO; GO:0043433; P:negative regulation of DNA-binding transcription factor activity; ISS:ARUK-UCL. DR GO; GO:0007399; P:nervous system development; IEA:Ensembl. DR GO; GO:0006355; P:regulation of DNA-templated transcription; TAS:ProtInc. DR GO; GO:0050767; P:regulation of neurogenesis; IBA:GO_Central. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central. DR Gene3D; 6.10.250.980; -; 1. DR Gene3D; 4.10.280.10; Helix-loop-helix DNA-binding domain; 1. DR InterPro; IPR011598; bHLH_dom. DR InterPro; IPR036638; HLH_DNA-bd_sf. DR InterPro; IPR003650; Orange_dom. DR PANTHER; PTHR10985; BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTOR, HES-RELATED; 1. DR PANTHER; PTHR10985:SF11; TRANSCRIPTION COFACTOR HES-6; 1. DR Pfam; PF07527; Hairy_orange; 1. DR Pfam; PF00010; HLH; 1. DR SMART; SM00353; HLH; 1. DR SUPFAM; SSF47459; HLH, helix-loop-helix DNA-binding domain; 1. DR SUPFAM; SSF158457; Orange domain-like; 1. DR PROSITE; PS50888; BHLH; 1. DR PROSITE; PS51054; ORANGE; 1. PE 1: Evidence at protein level; KW Alternative splicing; Developmental protein; Differentiation; Nucleus; KW Reference proteome; Repressor; Transcription; Transcription regulation. FT CHAIN 1..224 FT /note="Transcription cofactor HES-6" FT /id="PRO_0000127214" FT DOMAIN 25..77 FT /note="bHLH" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981" FT DOMAIN 96..129 FT /note="Orange" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00380" FT REGION 1..31 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 147..205 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 221..224 FT /note="WRPW motif" FT COMPBIAS 9..29 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT VAR_SEQ 57..58 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:10851137" FT /id="VSP_040128" FT VAR_SEQ 71..112 FT /note="VRRVQGVLRGRAREREQLQAEASERFAAGYIQCMHEVHTFVS -> SASSCR FT RKRASASLPATSSACTRCTRSCPRARPSTLPSLPSS (in isoform 4)" FT /evidence="ECO:0000305" FT /id="VSP_055615" FT VAR_SEQ 84..224 FT /note="EREQLQAEASERFAAGYIQCMHEVHTFVSTCQAIDATVAAELLNHLLESMPL FT REGSSFQDLLGDALAGPPRAPGRSGWPAGGAPGSPIPSPPGPGDDLCSDLEEAPEAELS FT QAPAEGPDLVPAALGSLTTAQIARSVWRPW -> GEWRRGGRGRRPRAPVTPARRRTSL FT PAPLSCRRRGLPPEQGAPPRLLGEPRPRGPGGLGHAVAAHRAGRGSLPPTLGPRARAAA FT GGSERALRCRLHPVHARGAHVRVHVPGHRRYRRCRAPEPSARVHAAA (in isoform FT 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011152" FT VAR_SEQ 113..224 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000305" FT /id="VSP_055616" FT VARIANT 218 FT /note="R -> Q (in dbSNP:rs3739061)" FT /id="VAR_019540" FT CONFLICT 205 FT /note="P -> R (in Ref. 1; BAA96082)" FT /evidence="ECO:0000305" FT CONFLICT 210..211 FT /note="SL -> AV (in Ref. 1; BAA96082)" FT /evidence="ECO:0000305" SQ SEQUENCE 224 AA; 24129 MW; E361BDDDCACBAD6F CRC64; MAPPAAPGRD RVGREDEDGW ETRGDRKARK PLVEKKRRAR INESLQELRL LLAGAEVQAK LENAEVLELT VRRVQGVLRG RAREREQLQA EASERFAAGY IQCMHEVHTF VSTCQAIDAT VAAELLNHLL ESMPLREGSS FQDLLGDALA GPPRAPGRSG WPAGGAPGSP IPSPPGPGDD LCSDLEEAPE AELSQAPAEG PDLVPAALGS LTTAQIARSV WRPW //