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Protein

Ubiquitin-like protein ISG15

Gene

Isg15

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Ubiquitin-like protein which plays a key role in the innate immune response to viral infection either via its conjugation to a target protein (ISGylation) or via its action as a free or unconjugated protein. ISGylation involves a cascade of enzymatic reactions involving E1, E2, and E3 enzymes which catalyze the conjugation of ISG15 to a lysine residue in the target protein. Its target proteins include SERPINA3G/SPI2A, JAK1, MAPK3/ERK1, PLCG1, TRIM25, STAT5A, MAPK1/ERK2 and globin. Can also isgylate: DDX58/RIG-I which inhibits its function in antiviral signaling response and EIF4E2 which enhances its cap structure-binding activity and translation-inhibition activity. Exhibits antiviral activity towards both DNA and RNA viruses, including influenza A and B virus, sindbis virus (SV) and herpes simplex type-1 (HHV-1). Plays a significant role in the control of neonatal Chikungunya virus (CHIKV) infection by acting as a putative immunomodulator of proinflammatory cytokines. Protects mice against the consequences of Chikungunya virus infection by downregulating the pathogenic cytokine response, often denoted as the cytokine storm. Plays a role in erythroid differentiation. The secreted form of ISG15 can: induce natural killer cell proliferation, act as a chemotactic factor for neutrophils and act as a IFN-gamma-inducing cytokine playing an essential role in antimycobacterial immunity.8 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei151Activating enzymeBy similarity1

GO - Molecular functioni

  • protein tag Source: MGI

GO - Biological processi

  • defense response to bacterium Source: UniProtKB
  • defense response to virus Source: UniProtKB
  • ISG15-protein conjugation Source: UniProtKB
  • modification-dependent protein catabolic process Source: MGI
  • negative regulation of protein ubiquitination Source: UniProtKB
  • negative regulation of viral genome replication Source: UniProtKB
  • positive regulation of bone mineralization Source: UniProtKB
  • positive regulation of erythrocyte differentiation Source: UniProtKB
  • regulation of interferon-gamma production Source: UniProtKB
  • response to type I interferon Source: UniProtKB

Keywordsi

Biological processAntiviral defense, Ubl conjugation pathway

Enzyme and pathway databases

ReactomeiR-MMU-1169408. ISG15 antiviral mechanism.
R-MMU-5656169. Termination of translesion DNA synthesis.

Names & Taxonomyi

Protein namesi
Recommended name:
Ubiquitin-like protein ISG15
Alternative name(s):
Interferon-induced 15 kDa protein
Interferon-induced 17 kDa protein
Short name:
IP17
Ubiquitin cross-reactive protein
Gene namesi
Name:Isg15
Synonyms:G1p2, Ucrp
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 4

Organism-specific databases

MGIiMGI:1855694. Isg15.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Secreted

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000359881 – 155Ubiquitin-like protein ISG15Add BLAST155
PropeptideiPRO_0000035989156 – 161Removed in mature formBy similarity6

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei76S-nitrosocysteine1 Publication1
Modified residuei144S-nitrosocysteine1 Publication1
Cross-linki155Glycyl lysine isopeptide (Gly-Lys) (interchain with K-? in acceptor proteins)PROSITE-ProRule annotation

Post-translational modificationi

S-nitrosylation decreases its dimerization, thereby increasing the availability as well as the solubility of monomeric ISG15 for its conjugation to cellular proteins.1 Publication
Induced as an inactive, precursor protein that is cleaved by specific proteases to expose the C-terminal diglycine (LRLRGG) motif. This motif is essential not only for its conjugation to substrates but also for its recognition by the relevant processing proteases (By similarity).By similarity

Keywords - PTMi

Disulfide bond, Isopeptide bond, S-nitrosylation

Proteomic databases

EPDiQ64339.
MaxQBiQ64339.
PaxDbiQ64339.
PRIDEiQ64339.

PTM databases

iPTMnetiQ64339.
PhosphoSitePlusiQ64339.

Expressioni

Inductioni

By type I interferons.

Gene expression databases

BgeeiENSMUSG00000035692.
CleanExiMM_ISG15.
ExpressionAtlasiQ64339. baseline and differential.
GenevisibleiQ64339. MM.

Interactioni

Subunit structurei

Homodimer; disulfide-linked. Interacts with, and is conjugated to its targets by the UBE1L (E1 enzyme) and UBE2E2 (E2 enzyme). Interacts with NEDD4 (By similarity).By similarity

Binary interactionsi

WithEntry#Exp.IntActNotes
Usp18Q9WTV62EBI-8345781,EBI-9119995

Protein-protein interaction databases

BioGridi782389. 44 interactors.
IntActiQ64339. 6 interactors.
MINTiMINT-4139466.
STRINGi10090.ENSMUSP00000082548.

Structurei

Secondary structure

1161
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi3 – 9Combined sources7
Turni10 – 12Combined sources3
Beta strandi14 – 19Combined sources6
Helixi25 – 36Combined sources12
Helixi40 – 42Combined sources3
Beta strandi43 – 47Combined sources5
Helixi59 – 61Combined sources3
Beta strandi68 – 73Combined sources6
Beta strandi80 – 85Combined sources6
Beta strandi87 – 89Combined sources3
Beta strandi91 – 96Combined sources6
Helixi102 – 113Combined sources12
Helixi117 – 119Combined sources3
Beta strandi120 – 124Combined sources5
Beta strandi131 – 134Combined sources4
Helixi135 – 138Combined sources4
Beta strandi145 – 150Combined sources6

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5CHFX-ray2.30A/B/C/D/E1-155[»]
5CHVX-ray3.00C/D1-155[»]
5CHWX-ray2.10A/B/C/D/E/F/G/H/I/J1-155[»]
5JZEX-ray2.47B/D79-154[»]
5TL7X-ray2.44A/C78-155[»]
5TLAX-ray3.24A/B/C/D/E/F/G/H/I/J1-150[»]
ProteinModelPortaliQ64339.
SMRiQ64339.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini2 – 76Ubiquitin-like 1PROSITE-ProRule annotationAdd BLAST75
Domaini77 – 155Ubiquitin-like 2PROSITE-ProRule annotationAdd BLAST79

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni151 – 155Involved in the ligation of specific target proteinsBy similarity5

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi150 – 155LRLRGGBy similarity6

Domaini

Both the Ubiquitin-like 1 and Ubiquitin-like 2 domains are required for its efficient conjugation to cellular proteins. The two domains play different roles in the ISGylation pathway: Ubiquitin-like 2 domain is necessary for the first two steps allowing the linking of ISG15 to the E1 and E2 enzymes while Ubiquitin-like 1 domain is essential for the final, E3-mediated transfer of ISG15, from the E2 to the Lys of the target protein (By similarity).By similarity

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG0001. Eukaryota.
COG5272. LUCA.
GeneTreeiENSGT00810000125435.
HOGENOMiHOG000233942.
HOVERGENiHBG000057.
InParanoidiQ64339.
KOiK12159.
OMAiFWLTFEG.
OrthoDBiEOG091G178I.
PhylomeDBiQ64339.
TreeFamiTF338379.

Family and domain databases

InterProiView protein in InterPro
IPR029071. Ubiquitin-like_domsf.
IPR000626. Ubiquitin_dom.
PfamiView protein in Pfam
PF00240. ubiquitin. 2 hits.
SMARTiView protein in SMART
SM00213. UBQ. 2 hits.
SUPFAMiSSF54236. SSF54236. 2 hits.
PROSITEiView protein in PROSITE
PS50053. UBIQUITIN_2. 2 hits.

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q64339-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MAWDLKVKML GGNDFLVSVT NSMTVSELKK QIAQKIGVPA FQQRLAHQTA
60 70 80 90 100
VLQDGLTLSS LGLGPSSTVM LVVQNCSEPL SILVRNERGH SNIYEVFLTQ
110 120 130 140 150
TVDTLKKKVS QREQVHEDQF WLSFEGRPME DKELLGEYGL KPQCTVIKHL
160
RLRGGGGDQC A
Length:161
Mass (Da):17,898
Last modified:January 23, 2007 - v4
Checksum:i9C70D9A507979171
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti111 – 115QREQV → SGTS in CAA39939 (Ref. 1) Curated5
Sequence conflicti111 – 115QREQV → SGTS in AAB02697 (Ref. 2) Curated5

Mass spectrometryi

Molecular mass is 17015 Da from positions 2 - 155. Determined by MALDI. 1 Publication

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X56602 mRNA. Translation: CAA39939.1.
U58202 Genomic DNA. Translation: AAB02697.1.
BC031424 mRNA. Translation: AAH31424.1.
BC083156 mRNA. Translation: AAH83156.1.
CCDSiCCDS51405.1.
PIRiS26434.
RefSeqiNP_056598.2. NM_015783.3.
UniGeneiMm.451527.
Mm.4950.

Genome annotation databases

EnsembliENSMUST00000085425; ENSMUSP00000082548; ENSMUSG00000035692.
GeneIDi100038882.
KEGGimmu:100038882.
UCSCiuc012dri.1. mouse.

Similar proteinsi

Entry informationi

Entry nameiISG15_MOUSE
AccessioniPrimary (citable) accession number: Q64339
Secondary accession number(s): Q8K0H3
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: January 23, 2007
Last modified: November 22, 2017
This is version 154 of the entry and version 4 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references