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Protein

E3 ISG15--protein ligase HERC5

Gene

HERC5

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Major E3 ligase for ISG15 conjugation. Acts as a positive regulator of innate antiviral response in cells induced by interferon. Functions as part of the ISGylation machinery that recognizes target proteins in a broad and relatively non-specific manner. Catalyzes ISGylation of IRF3 which results in sustained activation, it attenuates IRF3-PIN1 interaction, which antagonizes IRF3 ubiquitination and degradation, and boosts the antiviral response. Catalyzes ISGylation of influenza A viral NS1 which attenuates virulence; ISGylated NS1 fails to form homodimers and thus to interact with its RNA targets. Catalyzes ISGylation of papillomavirus type 16 L1 protein which results in dominant-negative effect on virus infectivity. Physically associated with polyribosomes, broadly modifies newly synthesized proteins in a cotranslational manner. In an interferon-stimulated cell, newly translated viral proteins are primary targets of ISG15.7 Publications

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Active sitei994 – 9941Glycyl thioester intermediatePROSITE-ProRule annotation

GO - Molecular functioni

  • ISG15 transferase activity Source: UniProtKB
  • ligase activity Source: UniProtKB-KW
  • poly(A) RNA binding Source: UniProtKB
  • ubiquitin-protein transferase activity Source: GO_Central

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Ligase

Keywords - Biological processi

Antiviral defense, Immunity, Innate immunity, Ubl conjugation pathway

Enzyme and pathway databases

ReactomeiR-HSA-1169408. ISG15 antiviral mechanism.
R-HSA-168928. RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways.
R-HSA-936440. Negative regulators of RIG-I/MDA5 signaling.

Names & Taxonomyi

Protein namesi
Recommended name:
E3 ISG15--protein ligase HERC5 (EC:6.3.2.-)
Alternative name(s):
Cyclin-E-binding protein 1
HECT domain and RCC1-like domain-containing protein 5
Gene namesi
Name:HERC5
Synonyms:CEB1, CEBP1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 4

Organism-specific databases

HGNCiHGNC:24368. HERC5.

Subcellular locationi

  • Cytoplasmperinuclear region 1 Publication

  • Note: Associated with the polyribosomes, probably via the 60S subunit.

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi994 – 9941C → A: Loss of activity; no effect on IRF3 interaction. 6 Publications

Organism-specific databases

PharmGKBiPA134973940.

Polymorphism and mutation databases

BioMutaiHERC5.
DMDMi296434523.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 10241024E3 ISG15--protein ligase HERC5PRO_0000206641Add
BLAST

Post-translational modificationi

ISGylated.1 Publication

Keywords - PTMi

Ubl conjugation

Proteomic databases

EPDiQ9UII4.
MaxQBiQ9UII4.
PaxDbiQ9UII4.
PRIDEiQ9UII4.

PTM databases

iPTMnetiQ9UII4.
PhosphoSiteiQ9UII4.

Expressioni

Tissue specificityi

Expressed in testis and to a lesser degree in brain, ovary and placenta. Found in most tissues at low levels.2 Publications

Inductioni

By IFNB1/IFN-beta. In endothelial cells, by TNF, IL1B/interleukin-1B and by bacterial lipopolysaccharides (LPS), hardly induced in other cells of the vascular wall such as primary smooth muscle cells and fibroblasts. By viral infection.2 Publications

Gene expression databases

BgeeiQ9UII4.
CleanExiHS_HERC5.
ExpressionAtlasiQ9UII4. baseline and differential.
GenevisibleiQ9UII4. HS.

Organism-specific databases

HPAiHPA043929.

Interactioni

Subunit structurei

Binds to CCNA1, CCNB1, CCND1 and CCNE1. Interacts with UBE2L6. Interacts with IRF3, this interaction is marginal in resting cells but enhanced upon viral infection. Interacts with influenza A virus NS1.5 Publications

Protein-protein interaction databases

BioGridi119365. 46 interactions.
DIPiDIP-44200N.
IntActiQ9UII4. 17 interactions.
MINTiMINT-4994259.
STRINGi9606.ENSP00000264350.

Structurei

3D structure databases

ProteinModelPortaliQ9UII4.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Repeati96 – 15560RCC1 1Add
BLAST
Repeati156 – 20853RCC1 2Add
BLAST
Repeati209 – 26052RCC1 3Add
BLAST
Repeati262 – 31251RCC1 4Add
BLAST
Repeati314 – 36451RCC1 5Add
BLAST
Domaini702 – 1024323HECTPROSITE-ProRule annotationAdd
BLAST

Sequence similaritiesi

Contains 1 HECT (E6AP-type E3 ubiquitin-protein ligase) domain.PROSITE-ProRule annotation
Contains 5 RCC1 repeats.PROSITE-ProRule annotation

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG0941. Eukaryota.
COG5021. LUCA.
COG5184. LUCA.
GeneTreeiENSGT00830000128260.
HOGENOMiHOG000208452.
HOVERGENiHBG050878.
InParanoidiQ9UII4.
OMAiIHFNVHW.
OrthoDBiEOG71VSRW.
PhylomeDBiQ9UII4.
TreeFamiTF315189.

Family and domain databases

Gene3Di2.130.10.30. 1 hit.
InterProiIPR000569. HECT_dom.
IPR009091. RCC1/BLIP-II.
IPR000408. Reg_chr_condens.
[Graphical view]
PfamiPF00632. HECT. 1 hit.
PF00415. RCC1. 4 hits.
[Graphical view]
PRINTSiPR00633. RCCNDNSATION.
SMARTiSM00119. HECTc. 1 hit.
[Graphical view]
SUPFAMiSSF50985. SSF50985. 1 hit.
SSF56204. SSF56204. 1 hit.
PROSITEiPS50237. HECT. 1 hit.
PS00626. RCC1_2. 2 hits.
PS50012. RCC1_3. 4 hits.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q9UII4-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MERRSRRKSR RNGRSTAGKA AATQPAKSPG AQLWLFPSAA GLHRALLRRV
60 70 80 90 100
EVTRQLCCSP GRLAVLERGG AGVQVHQLLA GSGGARTPKC IKLGKNMKIH
110 120 130 140 150
SVDQGAEHML ILSSDGKPFE YDNYSMKHLR FESILQEKKI IQITCGDYHS
160 170 180 190 200
LALSKGGELF AWGQNLHGQL GVGRKFPSTT TPQIVEHLAG VPLAQISAGE
210 220 230 240 250
AHSMALSMSG NIYSWGKNEC GQLGLGHTES KDDPSLIEGL DNQKVEFVAC
260 270 280 290 300
GGSHSALLTQ DGLLFTFGAG KHGQLGHNST QNELRPCLVA ELVGYRVTQI
310 320 330 340 350
ACGRWHTLAY VSDLGKVFSF GSGKDGQLGN GGTRDQLMPL PVKVSSSEEL
360 370 380 390 400
KLESHTSEKE LIMIAGGNQS ILLWIKKENS YVNLKRTIPT LNEGTVKRWI
410 420 430 440 450
ADVETKRWQS TKREIQEIFS SPACLTGSFL RKRRTTEMMP VYLDLNKARN
460 470 480 490 500
IFKELTQKDW ITNMITTCLK DNLLKRLPFH SPPQEALEIF FLLPECPMMH
510 520 530 540 550
ISNNWESLVV PFAKVVCKMS DQSSLVLEEY WATLQESTFS KLVQMFKTAV
560 570 580 590 600
ICQLDYWDES AEENGNVQAL LEMLKKLHRV NQVKCQLPES IFQVDELLHR
610 620 630 640 650
LNFFVEVCRR YLWKMTVDAS ENVQCCVIFS HFPFIFNNLS KIKLLHTDTL
660 670 680 690 700
LKIESKKHKA YLRSAAIEEE RESEFALRPT FDLTVRRNHL IEDVLNQLSQ
710 720 730 740 750
FENEDLRKEL WVSFSGEIGY DLGGVKKEFF YCLFAEMIQP EYGMFMYPEG
760 770 780 790 800
ASCMWFPVKP KFEKKRYFFF GVLCGLSLFN CNVANLPFPL ALFKKLLDQM
810 820 830 840 850
PSLEDLKELS PDLGKNLQTL LDDEGDNFEE VFYIHFNVHW DRNDTNLIPN
860 870 880 890 900
GSSITVNQTN KRDYVSKYIN YIFNDSVKAV YEEFRRGFYK MCDEDIIKLF
910 920 930 940 950
HPEELKDVIV GNTDYDWKTF EKNARYEPGY NSSHPTIVMF WKAFHKLTLE
960 970 980 990 1000
EKKKFLVFLT GTDRLQMKDL NNMKITFCCP ESWNERDPIR ALTCFSVLFL
1010 1020
PKYSTMETVE EALQEAINNN RGFG
Length:1,024
Mass (Da):116,852
Last modified:May 18, 2010 - v2
Checksum:i1449C51A58269A6C
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti204 – 2041M → T in AAR00320 (PubMed:15331633).Curated
Sequence conflicti419 – 4191F → S in AAR00320 (PubMed:15331633).Curated
Sequence conflicti453 – 4531K → R in BAA88519 (PubMed:10581175).Curated
Sequence conflicti498 – 4981M → V in BAA88519 (PubMed:10581175).Curated
Sequence conflicti498 – 4981M → V in AAR00320 (PubMed:15331633).Curated
Sequence conflicti498 – 4981M → V in AAI40717 (PubMed:15815621).Curated
Sequence conflicti513 – 5131A → T in AAR00320 (PubMed:15331633).Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti301 – 3011A → T.
Corresponds to variant rs17014143 [ dbSNP | Ensembl ].
VAR_057123

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB027289 mRNA. Translation: BAA88519.1.
AY337518 mRNA. Translation: AAR00320.1.
AC083829 Genomic DNA. No translation available.
BC140716 mRNA. Translation: AAI40717.1.
CCDSiCCDS3630.1.
RefSeqiNP_057407.2. NM_016323.3.
UniGeneiHs.26663.

Genome annotation databases

EnsembliENST00000264350; ENSP00000264350; ENSG00000138646.
GeneIDi51191.
KEGGihsa:51191.
UCSCiuc003hrt.5. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB027289 mRNA. Translation: BAA88519.1.
AY337518 mRNA. Translation: AAR00320.1.
AC083829 Genomic DNA. No translation available.
BC140716 mRNA. Translation: AAI40717.1.
CCDSiCCDS3630.1.
RefSeqiNP_057407.2. NM_016323.3.
UniGeneiHs.26663.

3D structure databases

ProteinModelPortaliQ9UII4.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi119365. 46 interactions.
DIPiDIP-44200N.
IntActiQ9UII4. 17 interactions.
MINTiMINT-4994259.
STRINGi9606.ENSP00000264350.

PTM databases

iPTMnetiQ9UII4.
PhosphoSiteiQ9UII4.

Polymorphism and mutation databases

BioMutaiHERC5.
DMDMi296434523.

Proteomic databases

EPDiQ9UII4.
MaxQBiQ9UII4.
PaxDbiQ9UII4.
PRIDEiQ9UII4.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000264350; ENSP00000264350; ENSG00000138646.
GeneIDi51191.
KEGGihsa:51191.
UCSCiuc003hrt.5. human.

Organism-specific databases

CTDi51191.
GeneCardsiHERC5.
H-InvDBHIX0200636.
HGNCiHGNC:24368. HERC5.
HPAiHPA043929.
MIMi608242. gene.
neXtProtiNX_Q9UII4.
PharmGKBiPA134973940.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0941. Eukaryota.
COG5021. LUCA.
COG5184. LUCA.
GeneTreeiENSGT00830000128260.
HOGENOMiHOG000208452.
HOVERGENiHBG050878.
InParanoidiQ9UII4.
OMAiIHFNVHW.
OrthoDBiEOG71VSRW.
PhylomeDBiQ9UII4.
TreeFamiTF315189.

Enzyme and pathway databases

ReactomeiR-HSA-1169408. ISG15 antiviral mechanism.
R-HSA-168928. RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways.
R-HSA-936440. Negative regulators of RIG-I/MDA5 signaling.

Miscellaneous databases

GeneWikiiHERC5.
GenomeRNAii51191.
NextBioi54182.
PROiQ9UII4.
SOURCEiSearch...

Gene expression databases

BgeeiQ9UII4.
CleanExiHS_HERC5.
ExpressionAtlasiQ9UII4. baseline and differential.
GenevisibleiQ9UII4. HS.

Family and domain databases

Gene3Di2.130.10.30. 1 hit.
InterProiIPR000569. HECT_dom.
IPR009091. RCC1/BLIP-II.
IPR000408. Reg_chr_condens.
[Graphical view]
PfamiPF00632. HECT. 1 hit.
PF00415. RCC1. 4 hits.
[Graphical view]
PRINTSiPR00633. RCCNDNSATION.
SMARTiSM00119. HECTc. 1 hit.
[Graphical view]
SUPFAMiSSF50985. SSF50985. 1 hit.
SSF56204. SSF56204. 1 hit.
PROSITEiPS50237. HECT. 1 hit.
PS00626. RCC1_2. 2 hits.
PS50012. RCC1_3. 4 hits.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "A novel human gene encoding HECT domain and RCC1-like repeats interacts with cyclins and is potentially regulated by the tumor suppressor proteins."
    Mitsui K., Nakanishi M., Ohtsuka S., Norwood T.H., Okabayashi K., Miyamoto C., Tanaka K., Yoshimura A., Ohtsubo M.
    Biochem. Biophys. Res. Commun. 266:115-122(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, INTERACTION WITH CCNA1; CCNB1; CCND1 AND CCNE1.
    Tissue: Embryonic kidney.
  2. "HERC5, a HECT E3 ubiquitin ligase tightly regulated in LPS activated endothelial cells."
    Kroismayr R., Baranyi U., Stehlik C., Dorfleutner A., Binder B.R., Lipp J.
    J. Cell Sci. 117:4749-4756(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], MUTAGENESIS OF CYS-994, TISSUE SPECIFICITY, INDUCTION.
  3. "Generation and annotation of the DNA sequences of human chromosomes 2 and 4."
    Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H.
    , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K.
    Nature 434:724-731(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  4. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Tissue: Brain.
  5. "Identification and Herc5-mediated ISGylation of novel target proteins."
    Takeuchi T., Inoue S., Yokosawa H.
    Biochem. Biophys. Res. Commun. 348:473-477(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  6. "Herc5, an interferon-induced HECT E3 enzyme, is required for conjugation of ISG15 in human cells."
    Dastur A., Beaudenon S., Kelley M., Krug R.M., Huibregtse J.M.
    J. Biol. Chem. 281:4334-4338(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, MUTAGENESIS OF CYS-994.
  7. "HERC5 is an IFN-induced HECT-type E3 protein ligase that mediates type I IFN-induced ISGylation of protein targets."
    Wong J.J., Pung Y.F., Sze N.S., Chin K.C.
    Proc. Natl. Acad. Sci. U.S.A. 103:10735-10740(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, MUTAGENESIS OF CYS-994, ISGYLATION, INDUCTION BY IFNB1, INTERACTION WITH ISGYLATED HSPA8 AND TXNRD1.
  8. "Herc5 attenuates influenza A virus by catalyzing ISGylation of viral NS1 protein."
    Tang Y., Zhong G., Zhu L., Liu X., Shan Y., Feng H., Bu Z., Chen H., Wang C.
    J. Immunol. 184:5777-5790(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, MUTAGENESIS OF CYS-994.
  9. "Positive regulation of interferon regulatory factor 3 activation by Herc5 via ISG15 modification."
    Shi H.X., Yang K., Liu X., Liu X.Y., Wei B., Shan Y.F., Zhu L.H., Wang C.
    Mol. Cell. Biol. 30:2424-2436(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, MUTAGENESIS OF CYS-994, INTERACTION WITH IRF3.
  10. "The ISG15 conjugation system broadly targets newly synthesized proteins: implications for the antiviral function of ISG15."
    Durfee L.A., Lyon N., Seo K., Huibregtsesend J.M.
    Mol. Cell 38:722-732(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH 60S SUBUNIT, MUTAGENESIS OF CYS-994.
  11. "ISG15 conjugation system targets the viral NS1 protein in influenza A virus-infected cells."
    Zhao C., Hsiang T.Y., Kuo R.L., Krug R.M.
    Proc. Natl. Acad. Sci. U.S.A. 107:2253-2258(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH INFLUENZA A VIRUS NS1.

Entry informationi

Entry nameiHERC5_HUMAN
AccessioniPrimary (citable) accession number: Q9UII4
Secondary accession number(s): B2RTQ1, Q69G20
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 10, 2004
Last sequence update: May 18, 2010
Last modified: April 13, 2016
This is version 131 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Caution

Was thought to be a ubiquitin ligase ubiquitinated by UBE2D1, but was confirmed by numerous studies that it's main function is as E3 ISG15 ligase.1 Publication

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 4
    Human chromosome 4: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.