HERC2

Protein identityUniProt · HPA

UniProt accession

O95714

Gene

HERC2

Ensembl

ENSG00000128731

Chromosome

15

Canonical length

4834 aa

Protein class

Disease related genes, Enzymes, Human disease related genes, Metabolic proteins, Potential drug targets, Predicted intracellular proteins, Predicted membrane proteins

Subcellular location

Plasma membrane,Cytosol

OverviewNCBI Gene

This gene belongs to the HERC gene family that encodes a group of unusually large proteins, which contain multiple structural domains. All members have at least 1 copy of an N-terminal region showing homology to the cell cycle regulator RCC1 and a C-terminal HECT (homologous to E6-AP C terminus) domain found in a number of E3 ubiquitin protein ligases. Genetic variations in this gene are associated with skin/hair/eye pigmentation variability. Multiple pseudogenes of this gene are located on chromosomes 15 and 16. [provided by RefSeq, Mar 2012]

Canonical amino-acid sequenceUniProt

4834 residues, UniProt reviewed canonical sequence.

>O95714|HERC2
     1  MPSESFCLAA QARLDSKWLK TDIQLAFTRD GLCGLWNEMV KDGEIVYTGT ESTQNGELPP
    61  RKDDSVEPSG TKKEDLNDKE KKDEEETPAP IYRAKSILDS WVWGKQPDVN ELKECLSVLV
   121  KEQQALAVQS ATTTLSALRL KQRLVILERY FIALNRTVFQ ENVKVKWKSS GISLPPVDKK
   181  SSRPAGKGVE GLARVGSRAA LSFAFAFLRR AWRSGEDADL CSELLQESLD ALRALPEASL
   241  FDESTVSSVW LEVVERATRF LRSVVTGDVH GTPATKGPGS IPLQDQHLAL AILLELAVQR
   301  GTLSQMLSAI LLLLQLWDSG AQETDNERSA QGTSAPLLPL LQRFQSIICR KDAPHSEGDM
   361  HLLSGPLSPN ESFLRYLTLP QDNELAIDLR QTAVVVMAHL DRLATPCMPP LCSSPTSHKG
   421  SLQEVIGWGL IGWKYYANVI GPIQCEGLAN LGVTQIACAE KRFLILSRNG RVYTQAYNSD
   481  TLAPQLVQGL ASRNIVKIAA HSDGHHYLAL AATGEVYSWG CGDGGRLGHG DTVPLEEPKV
   541  ISAFSGKQAG KHVVHIACGS TYSAAITAEG ELYTWGRGNY GRLGHGSSED EAIPMLVAGL
   601  KGLKVIDVAC GSGDAQTLAV TENGQVWSWG DGDYGKLGRG GSDGCKTPKL IEKLQDLDVV
   661  KVRCGSQFSI ALTKDGQVYS WGKGDNQRLG HGTEEHVRYP KLLEGLQGKK VIDVAAGSTH
   721  CLALTEDSEV HSWGSNDQCQ HFDTLRVTKP EPAALPGLDT KHIVGIACGP AQSFAWSSCS
   781  EWSIGLRVPF VVDICSMTFE QLDLLLRQVS EGMDGSADWP PPQEKECVAV ATLNLLRLQL
   841  HAAISHQVDP EFLGLGLGSI LLNSLKQTVV TLASSAGVLS TVQSAAQAVL QSGWSVLLPT
   901  AEERARALSA LLPCAVSGNE VNISPGRRFM IDLLVGSLMA DGGLESALHA AITAEIQDIE
   961  AKKEAQKEKE IDEQEANAST FHRSRTPLDK DLINTGICES SGKQCLPLVQ LIQQLLRNIA
  1021  SQTVARLKDV ARRISSCLDF EQHSRERSAS LDLLLRFQRL LISKLYPGES IGQTSDISSP
  1081  ELMGVGSLLK KYTALLCTHI GDILPVAASI ASTSWRHFAE VAYIVEGDFT GVLLPELVVS
  1141  IVLLLSKNAG LMQEAGAVPL LGGLLEHLDR FNHLAPGKER DDHEELAWPG IMESFFTGQN
  1201  CRNNEEVTLI RKADLENHNK DGGFWTVIDG KVYDIKDFQT QSLTGNSILA QFAGEDPVVA
  1261  LEAALQFEDT RESMHAFCVG QYLEPDQEIV TIPDLGSLSS PLIDTERNLG LLLGLHASYL
  1321  AMSTPLSPVE IECAKWLQSS IFSGGLQTSQ IHYSYNEEKD EDHCSSPGGT PASKSRLCSH
  1381  RRALGDHSQA FLQAIADNNI QDHNVKDFLC QIERYCRQCH LTTPIMFPPE HPVEEVGRLL
  1441  LCCLLKHEDL GHVALSLVHA GALGIEQVKH RTLPKSVVDV CRVVYQAKCS LIKTHQEQGR
  1501  SYKEVCAPVI ERLRFLFNEL RPAVCNDLSI MSKFKLLSSL PRWRRIAQKI IRERRKKRVP
  1561  KKPESTDDEE KIGNEESDLE EACILPHSPI NVDKRPIAIK SPKDKWQPLL STVTGVHKYK
  1621  WLKQNVQGLY PQSPLLSTIA EFALKEEPVD VEKMRKCLLK QLERAEVRLE GIDTILKLAS
  1681  KNFLLPSVQY AMFCGWQRLI PEGIDIGEPL TDCLKDVDLI PPFNRMLLEV TFGKLYAWAV
  1741  QNIRNVLMDA SAKFKELGIQ PVPLQTITNE NPSGPSLGTI PQARFLLVML SMLTLQHGAN
  1801  NLDLLLNSGM LALTQTALRL IGPSCDNVEE DMNASAQGAS ATVLEETRKE TAPVQLPVSG
  1861  PELAAMMKIG TRVMRGVDWK WGDQDGPPPG LGRVIGELGE DGWIRVQWDT GSTNSYRMGK
  1921  EGKYDLKLAE LPAAAQPSAE DSDTEDDSEA EQTERNIHPT AMMFTSTINL LQTLCLSAGV
  1981  HAEIMQSEAT KTLCGLLRML VESGTTDKTS SPNRLVYREQ HRSWCTLGFV RSIALTPQVC
  2041  GALSSPQWIT LLMKVVEGHA PFTATSLQRQ ILAVHLLQAV LPSWDKTERA RDMKCLVEKL
  2101  FDFLGSLLTT CSSDVPLLRE STLRRRRVRP QASLTATHSS TLAEEVVALL RTLHSLTQWN
  2161  GLINKYINSQ LRSITHSFVG RPSEGAQLED YFPDSENPEV GGLMAVLAVI GGIDGRLRLG
  2221  GQVMHDEFGE GTVTRITPKG KITVQFSDMR TCRVCPLNQL KPLPAVAFNV NNLPFTEPML
  2281  SVWAQLVNLA GSKLEKHKIK KSTKQAFAGQ VDLDLLRCQQ LKLYILKAGR ALLSHQDKLR
  2341  QILSQPAVQE TGTVHTDDGA VVSPDLGDMS PEGPQPPMIL LQQLLASATQ PSPVKAIFDK
  2401  QELEAAALAV CQCLAVESTH PSSPGFEDCS SSEATTPVAV QHIRPARVKR RKQSPVPALP
  2461  IVVQLMEMGF SRRNIEFALK SLTGASGNAS SLPGVEALVG WLLDHSDIQV TELSDADTVS
  2521  DEYSDEEVVE DVDDAAYSMS TGAVVTESQT YKKRADFLSN DDYAVYVREN IQVGMMVRCC
  2581  RAYEEVCEGD VGKVIKLDRD GLHDLNVQCD WQQKGGTYWV RYIHVELIGY PPPSSSSHIK
  2641  IGDKVRVKAS VTTPKYKWGS VTHQSVGVVK AFSANGKDII VDFPQQSHWT GLLSEMELVP
  2701  SIHPGVTCDG CQMFPINGSR FKCRNCDDFD FCETCFKTKK HNTRHTFGRI NEPGQSAVFC
  2761  GRSGKQLKRC HSSQPGMLLD SWSRMVKSLN VSSSVNQASR LIDGSEPCWQ SSGSQGKHWI
  2821  RLEIFPDVLV HRLKMIVDPA DSSYMPSLVV VSGGNSLNNL IELKTININP SDTTVPLLND
  2881  CTEYHRYIEI AIKQCRSSGI DCKIHGLILL GRIRAEEEDL AAVPFLASDN EEEEDEKGNS
  2941  GSLIRKKAAG LESAATIRTK VFVWGLNDKD QLGGLKGSKI KVPSFSETLS ALNVVQVAGG
  3001  SKSLFAVTVE GKVYACGEAT NGRLGLGISS GTVPIPRQIT ALSSYVVKKV AVHSGGRHAT
  3061  ALTVDGKVFS WGEGDDGKLG HFSRMNCDKP RLIEALKTKR IRDIACGSSH SAALTSSGEL
  3121  YTWGLGEYGR LGHGDNTTQL KPKMVKVLLG HRVIQVACGS RDAQTLALTD EGLVFSWGDG
  3181  DFGKLGRGGS EGCNIPQNIE RLNGQGVCQI ECGAQFSLAL TKSGVVWTWG KGDYFRLGHG
  3241  SDVHVRKPQV VEGLRGKKIV HVAVGALHCL AVTDSGQVYA WGDNDHGQQG NGTTTVNRKP
  3301  TLVQGLEGQK ITRVACGSSH SVAWTTVDVA TPSVHEPVLF QTARDPLGAS YLGVPSDADS
  3361  SAASNKISGA SNSKPNRPSL AKILLSLDGN LAKQQALSHI LTALQIMYAR DAVVGALMPA
  3421  AMIAPVECPS FSSAAPSDAS AMASPMNGEE CMLAVDIEDR LSPNPWQEKR EIVSSEDAVT
  3481  PSAVTPSAPS ASARPFIPVT DDLGAASIIA ETMTKTKEDV ESQNKAAGPE PQALDEFTSL
  3541  LIADDTRVVV DLLKLSVCSR AGDRGRDVLS AVLSGMGTAY PQVADMLLEL CVTELEDVAT
  3601  DSQSGRLSSQ PVVVESSHPY TDDTSTSGTV KIPGAEGLRV EFDRQCSTER RHDPLTVMDG
  3661  VNRIVSVRSG REWSDWSSEL RIPGDELKWK FISDGSVNGW GWRFTVYPIM PAAGPKELLS
  3721  DRCVLSCPSM DLVTCLLDFR LNLASNRSIV PRLAASLAAC AQLSALAASH RMWALQRLRK
  3781  LLTTEFGQSI NINRLLGEND GETRALSFTG SALAALVKGL PEALQRQFEY EDPIVRGGKQ
  3841  LLHSPFFKVL VALACDLELD TLPCCAETHK WAWFRRYCMA SRVAVALDKR TPLPRLFLDE
  3901  VAKKIRELMA DSENMDVLHE SHDIFKREQD EQLVQWMNRR PDDWTLSAGG SGTIYGWGHN
  3961  HRGQLGGIEG AKVKVPTPCE ALATLRPVQL IGGEQTLFAV TADGKLYATG YGAGGRLGIG
  4021  GTESVSTPTL LESIQHVFIK KVAVNSGGKH CLALSSEGEV YSWGEAEDGK LGHGNRSPCD
  4081  RPRVIESLRG IEVVDVAAGG AHSACVTAAG DLYTWGKGRY GRLGHSDSED QLKPKLVEAL
  4141  QGHRVVDIAC GSGDAQTLCL TDDDTVWSWG DGDYGKLGRG GSDGCKVPMK IDSLTGLGVV
  4201  KVECGSQFSV ALTKSGAVYT WGKGDYHRLG HGSDDHVRRP RQVQGLQGKK VIAIATGSLH
  4261  CVCCTEDGEV YTWGDNDEGQ LGDGTTNAIQ RPRLVAALQG KKVNRVACGS AHTLAWSTSK
  4321  PASAGKLPAQ VPMEYNHLQE IPIIALRNRL LLLHHLSELF CPCIPMFDLE GSLDETGLGP
  4381  SVGFDTLRGI LISQGKEAAF RKVVQATMVR DRQHGPVVEL NRIQVKRSRS KGGLAGPDGT
  4441  KSVFGQMCAK MSSFGPDSLL LPHRVWKVKF VGESVDDCGG GYSESIAEIC EELQNGLTPL
  4501  LIVTPNGRDE SGANRDCYLL SPAARAPVHS SMFRFLGVLL GIAIRTGSPL SLNLAEPVWK
  4561  QLAGMSLTIA DLSEVDKDFI PGLMYIRDNE ATSEEFEAMS LPFTVPSASG QDIQLSSKHT
  4621  HITLDNRAEY VRLAINYRLH EFDEQVAAVR EGMARVVPVP LLSLFTGYEL ETMVCGSPDI
  4681  PLHLLKSVAT YKGIEPSASL IQWFWEVMES FSNTERSLFL RFVWGRTRLP RTIADFRGRD
  4741  FVIQVLDKYN PPDHFLPESY TCFFLLKLPR YSCKQVLEEK LKYAIHFCKS IDTDDYARIA
  4801  LTGEPAADDS SDDSDNEDVD SFASDSTQDY LTGH

LocalizationUniProt · AlphaFold · HPA

Whether an antibody against HERC2 can act on the native protein depends on physical access: surface and secreted proteins are reachable by circulating antibodies, intracellular proteins usually are not.

Antibody reachability

Intracellular

Secreted

No

Transmembrane segments

0

Mean surface accessibility (rSASA)

0

Highest tissue expression

9.1 nTPM

Expression across tissuesHPA

DiseaseUniProt · ClinVar · IEDB · PubMed

Four sources answering four different questions about HERC2.

Disease | AllUniProt

Conditions HERC2 is implicated in, by any mechanism.

• Intellectual developmental disorder, autosomal recessive 38 (MRT38) MIM:615516

Disease | GeneticClinVar

25 pathogenic / likely-pathogenic of 1,317 ClinVar records.

Conditions with pathogenic or likely-pathogenic variants.

• Developmental delay with autism spectrum disorder and gait instability
• SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES
• Prader-Willi syndrome
• 8 conditions
• See cases

Genetic constraint and essentialitygnomAD · DepMap

Does the body need this protein intact? Low LOEUF or a strong DepMap dependency means loss or blockade of the protein is likely to be felt.

gnomAD LOEUF (loss-of-function intolerance)

0.2

gnomAD pLI

1

gnomAD missense Z

4.42

DepMap mean gene effect

-0.1

DepMap dependency class

selective

Cancer expressionTCGA

Across TCGA tumor cohorts, this protein is over-expressed in roughly 3% of surveyed tumor types (aggregate summary; per-cohort expression, alteration, and survival load in the interactive view).

OntologyGO

Biological processes

• DNA damage response
• DNA repair
• intracellular protein transport
• negative regulation of Notch signaling pathway
• neuron differentiation
• proteasome-mediated ubiquitin-dependent protein catabolic process
• protein stabilization
• protein ubiquitination
• spermatogenesis

Molecular functions

• guanyl-nucleotide exchange factor activity
• SUMO binding
• ubiquitin protein ligase activity
• ubiquitin protein ligase binding
• zinc ion binding

Cellular components

• centriole
• cytoplasm
• cytosol
• membrane
• nucleoplasm
• nucleus
• plasma membrane

Protein domainsUniProt · Pfam · InterPro

• Regulator of chromosome condensation, RCC1
• Zinc finger, ZZ-type
• HECT domain
• Cytochrome b5-like heme/steroid binding domain
• APC10/DOC domain
• Beta-propeller repeat TECPR
• Galactose-binding-like domain superfamily
• Regulator of chromosome condensation 1/beta-lactamase-inhibitor protein II
• Mib-herc2
• Large ribosomal subunit protein uL2, domain 2
• CPH domain
• HECT, E3 ligase catalytic domain
• Cytochrome b5-like heme/steroid binding domain superfamily
• Mib/herc2 domain superfamily
• Zinc finger, ZZ-type superfamily
• Diverse Signaling and Regulatory Domain-Containing Protein
• RCC1-like domain
• Cytochrome b5-like Heme/Steroid binding domain
• Regulator of chromosome condensation (RCC1) repeat
• Zinc finger, ZZ type
• HECT-domain (ubiquitin-transferase)
• Anaphase-promoting complex, subunit 10 (APC10)
• Mib_herc2
• Mouse development and cellular proliferation protein Cullin-7
• RCC1-like domain
• HERC2, APC10 domain
• HERC2, zinc finger, ZZ-type

KeywordsUniProt

• Coiled coil
• Cytoplasm
• Cytoskeleton
• DNA damage
• DNA repair
• Intellectual disability
• Metal-binding
• Nucleus
• Phosphoprotein
• Repeat
• Transferase
• Ubl conjugation
• Ubl conjugation pathway
• Zinc
• Zinc-finger

InteractionsUniProt · HPA

Protein binding partners of HERC2 in the human serome: UniProt-annotated complex subunits plus reported interactors. Each links to its own Seroatlas record.

• NEURL4
• XPA
• DBNL
• EIF3L
• FBXL5
• NAT10
• RAF1
• SPZ1
• SSBP1
• ZNRD2