P05161 (ISG15_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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
Short name=hUCRP

Gene names

Name:	ISG15
Synonyms:	G1P2, UCRP

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	165 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Ubiquitin-like protein that is conjugated to intracellular target proteins after IFN-alpha or IFN-beta stimulation. Its enzymatic pathway is partially distinct from that of ubiquitin, differing in substrate specificity and interaction with ligating enzymes. ISG15 conjugation pathway uses a dedicated E1 enzyme, but seems to converge with the Ub conjugation pathway at the level of a specific E2 enzyme. Targets include STAT1, SERPINA3G/SPI2A, JAK1, MAPK3/ERK1, PLCG1, EIF2AK2/PKR, MX1/MxA, and RIG-1. Deconjugated by USP18/UBP43. Shows specific chemotactic activity towards neutrophils and activates them to induce release of eosinophil chemotactic factors. May serve as a trans-acting binding factor directing the association of ligated target proteins to intermediate filaments. May also be involved in autocrine, paracrine and endocrine mechanisms, as in cell-to-cell signaling, possibly partly by inducing IFN-gamma secretion by monocytes and macrophages. Seems to display antiviral activity during viral infections. Ref.12 Ref.13 Ref.14 Ref.15 Ref.20 Ref.21 In response to IFN-tau secreted by the conceptus, may ligate to and regulate proteins involved in the release of prostaglandin F2-alpha (PGF), and thus prevent lysis of the corpus luteum and maintain the pregnancy By similarity. Ref.12 Ref.13 Ref.14 Ref.15 Ref.20 Ref.21
Subunit structure	Interacts with, and is conjugated to its targets by the UBE1L (E1 enzyme) and UBE2E2 (E2 enzyme) Probable. Interaction with influenza B NS1 protein inhibits this conjugation. Ref.17 Ref.19
Subcellular location	Cytoplasm. Secreted. Note: UCRP conjugates seem to be noncovalently associated with the intermediate filaments and distributed in a punctate pattern. Also secreted.
Tissue specificity	Detected in lymphoid cells, striated and smooth muscle, several epithelia and neurons. Ref.16
Induction	By type I interferons.
Sequence similarities	Contains 2 ubiquitin-like domains.

Ontologies

Keywords
Biological process	Antiviral defense Host-virus interaction Ubl conjugation pathway
Cellular component	Cytoplasm Secreted
Coding sequence diversity	Polymorphism
Domain	Repeat
PTM	Isopeptide bond
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	ISG15-protein conjugation Inferred from direct assay PubMed 16122702. Source: HGNC cell-cell signaling Non-traceable author statement. Source: UniProtKB defense response to virus Inferred from electronic annotation. Source: UniProtKB-KW modification-dependent protein catabolic process Inferred from electronic annotation. Source: Compara negative regulation of type I interferon production Traceable author statement. Source: Reactome type I interferon-mediated signaling pathway Traceable author statement. Source: Reactome virus-host interaction Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	cytosol Traceable author statement. Source: Reactome extracellular space Non-traceable author statement. Source: UniProtKB
Molecular_function	protein tag Inferred from electronic annotation. Source: Compara
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.10

Chain

2 – 157

156

Ubiquitin-like protein ISG15

PRO_0000035986

Propeptide

158 – 165

8

Removed in mature form

PRO_0000035987

Regions

Domain

2 – 78

77

Ubiquitin-like 1

Domain

79 – 157

79

Ubiquitin-like 2

Region

153 – 157

5

Involved in the ligation of specific target proteins By similarity

Sites

Binding site

153

1

Activating enzyme By similarity

Amino acid modifications

Cross-link

157

Glycyl lysine isopeptide (Gly-Lys) (interchain with K-? in acceptor proteins) By similarity

Natural variations

Natural variant

83

1

S → N. Ref.5 Ref.6 Ref.9
Corresponds to variant rs1921 [ dbSNP | Ensembl ].

VAR_016181

Experimental info

Sequence conflict

35

1

K → N in AAA36128. Ref.2

Secondary structure

1

.

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.

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.

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165

Helix Strand Turn

Details...

Beta strand

4 – 9

6

Beta strand

14 – 18

5

Helix

25 – 36

12

Helix

40 – 42

3

Beta strand

43 – 48

6

Beta strand

56 – 58

3

Helix

60 – 63

4

Beta strand

70 – 75

6

Beta strand

82 – 87

6

Beta strand

93 – 98

6

Helix

104 – 115

12

Helix

119 – 121

3

Beta strand

122 – 126

5

Helix

137 – 140

4

Beta strand

147 – 152

6

Sequences

	Sequence		Length	Mass (Da)
	P05161 [UniParc]. Last modified January 23, 2007. Version 5. Checksum: B6858A15AB0FFFDE	FASTA	165	17,888
	10 20 30 40 50 60 MGWDLTVKML AGNEFQVSLS SSMSVSELKA QITQKIGVHA FQQRLAVHPS GVALQDRVPL 70 80 90 100 110 120 ASQGLGPGST VLLVVDKCDE PLSILVRNNK GRSSTYEVRL TQTVAHLKQQ VSGLEGVQDD 130 140 150 160 LFWLTFEGKP LEDQLPLGEY GLKPLSTVFM NLRLRGGGTE PGGRS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular characterization of the interferon-induced 15-kDa protein. Molecular cloning and nucleotide and amino acid sequence." Blomstrom D.C., Fahey D., Kutny R., Korant B.D., Knight E. Jr. J. Biol. Chem. 261:8811-8816(1986) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Interferon-induced transcription of a gene encoding a 15-kDa protein depends on an upstream enhancer element." Reich N., Evans B., Levy D., Fahey D., Knight E. Jr., Darnell J.E. Jr. Proc. Natl. Acad. Sci. U.S.A. 84:6394-6398(1987) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"A 15-kDa interferon-induced protein is derived by COOH-terminal processing of a 17-kDa precursor." Knight E. Jr., Fahey D., Cordova B., Hillman M. Jr., Kutny R., Reich N., Blomstrom D.C. J. Biol. Chem. 263:4520-4522(1988) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEOLYTIC PROCESSING.
[4]	Erratum Knight E. Jr., Fahey D., Cordova B., Hillman M. Jr., Kutny R., Reich N., Blomstrom D.C. J. Biol. Chem. 263:10040-10040(1988)
[5]	"Conjugation by ubiquitin-like proteins." Kamitani T., Fukuda-Kamitani T. Submitted (OCT-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT ASN-83. Tissue: Testis.
[6]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT ASN-83.
[7]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[9]	"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], VARIANT ASN-83. Tissue: Colon.
[10]	"A 15-kD interferon-induced protein and its 17-kD precursor: expression in Escherichia coli, purification, and characterization." Feltham N., Hillman M. Jr., Cordova B., Fahey D., Larsen B., Blomstrom D.C., Knight E. Jr. J. Interferon Res. 9:493-507(1989) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-38 AND 151-165, PROTEOLYTIC PROCESSING.
[11]	"Interferon induces a 15-kilodalton protein exhibiting marked homology to ubiquitin." Haas A.L., Ahrens P., Bright P.M., Ankel H. J. Biol. Chem. 262:11315-11323(1987) [PubMed] [Europe PMC] [Abstract] Cited for: SIMILARITY TO UBIQUITIN.
[12]	"The interferon-inducible 15-kDa ubiquitin homolog conjugates to intracellular proteins." Loeb K.R., Haas A.L. J. Biol. Chem. 267:7806-7813(1992) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[13]	"Conjugates of ubiquitin cross-reactive protein distribute in a cytoskeletal pattern." Loeb K.R., Haas A.L. Mol. Cell. Biol. 14:8408-8419(1994) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[14]	"Conjugation of the 15-kDa interferon-induced ubiquitin homolog is distinct from that of ubiquitin." Narasimhan J., Potter J.L., Haas A.L. J. Biol. Chem. 271:324-330(1996) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[15]	"IFN-induced 15-kDa protein is released from human lymphocytes and monocytes." Knight E. Jr., Cordova B. J. Immunol. 146:2280-2284(1991) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[16]	"Immunohistochemical localization of ubiquitin cross-reactive protein in human tissues." Lowe J., McDermott H., Loeb K., Landon M., Haas A.L., Mayer R.J. J. Pathol. 177:163-169(1995) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY.
[17]	"Influenza B virus NS1 protein inhibits conjugation of the interferon (IFN)-induced ubiquitin-like ISG15 protein." Yuan W., Krug R.M. EMBO J. 20:362-371(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH UBE1L AND INFLUENZA B NS1.
[18]	"UBP43 (USP18) specifically removes ISG15 from conjugated proteins." Malakhov M.P., Malakhova O.A., Kim K.I., Ritchie K.J., Zhang D.-E. J. Biol. Chem. 277:9976-9981(2002) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION.
[19]	"The UbcH8 ubiquitin E2 enzyme is also the E2 enzyme for ISG15, an IFN-alpha/beta-induced ubiquitin-like protein." Zhao C., Beaudenon S.L., Kelley M.L., Waddell M.B., Yuan W., Schulman B.A., Huibregtse J.M., Krug R.M. Proc. Natl. Acad. Sci. U.S.A. 101:7578-7582(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH UBE2E2.
[20]	"Identification of interferon-stimulated gene 15 as an antiviral molecule during Sindbis virus infection in vivo." Lenschow D.J., Giannakopoulos N.V., Gunn L.J., Johnston C., O'Guin A.K., Schmidt R.E., Levine B., Virgin H.W. IV J. Virol. 79:13974-13983(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[21]	"Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways." Zhao C., Denison C., Huibregtse J.M., Gygi S.P., Krug R.M. Proc. Natl. Acad. Sci. U.S.A. 102:10200-10205(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[22]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[23]	"Crystal structure of the interferon-induced ubiquitin-like protein ISG15." Narasimhan J., Wang M., Fu Z., Klein J.M., Haas A.L., Kim J.J. J. Biol. Chem. 280:27356-27365(2005) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 1-155 OF MUTANT SER-78.
[24]	"Solution NMR structure of the C-terminal domain of the interferon alpha-inducible ISG15 protein from Homo sapiens." Northeast structural genomics consortium (NESG) Submitted (FEB-2009) to the PDB data bank Cited for: STRUCTURE BY NMR OF 79-157.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M13755 mRNA. Translation: AAA36038.1.
M21786 Genomic DNA. Translation: AAA36128.1.
AY168648 mRNA. Translation: AAN86983.1.
BT007297 mRNA. Translation: AAP35961.1.
AL645608 Genomic DNA. Translation: CAI15574.1.
CH471183 Genomic DNA. Translation: EAW56295.1.
BC009507 mRNA. Translation: AAH09507.1.

IPI

IPI00375631.

PIR

A28138. A28304.

RefSeq

NP_005092.1. NM_005101.3.

UniGene

Hs.458485.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1Z2M	X-ray	2.50	A	1-155	[»]
2HJ8	NMR	-	A	79-157	[»]
3PHX	X-ray	1.60	B	79-156	[»]
3PSE	X-ray	2.30	B	1-156	[»]
3R66	X-ray	2.30	C/D	1-157	[»]
3RT3	X-ray	2.01	B	1-158	[»]
3SDL	X-ray	2.29	C/D	1-157	[»]

ProteinModelPortal

P05161.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29814N.

IntAct

P05161. 2 interactions.

MINT

MINT-1440156.

STRING

9606.ENSP00000368699.

PTM databases

PhosphoSite

P05161.

Polymorphism databases

DMDM

52001470.

Proteomic databases

PaxDb

P05161.

PeptideAtlas

P05161.

PRIDE

P05161.

Protocols and materials databases

DNASU

9636.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000379389; ENSP00000368699; ENSG00000187608.

GeneID

9636.

KEGG

hsa:9636.

UCSC

uc001acj.4. human.

Organism-specific databases

CTD

9636.

GeneCards

GC01P000938.

HGNC

HGNC:4053. ISG15.

HPA

HPA004627.

MIM

147571. gene.

neXtProt

NX_P05161.

PharmGKB

PA28465.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG5272.

HOGENOM

HOG000233942.

HOVERGEN

HBG000057.

InParanoid

P05161.

KO

K12159.

OMA

FWLTFEG.

OrthoDB

EOG4CNQSF.

PhylomeDB

P05161.

Enzyme and pathway databases

Reactome

REACT_6900. Immune System.

Gene expression databases

Bgee

P05161.

CleanEx

HS_ISG15.

Genevestigator

P05161.

GermOnline

ENSG00000187608. Homo sapiens.

Family and domain databases

InterPro

IPR000626. Ubiquitin.
IPR019956. Ubiquitin_subgr.
IPR019955. Ubiquitin_supergroup.
[Graphical view]

Pfam

PF00240. ubiquitin. 2 hits.
[Graphical view]

PRINTS

PR00348. UBIQUITIN.

SMART

SM00213. UBQ. 2 hits.
[Graphical view]

PROSITE

PS50053. UBIQUITIN_2. 2 hits.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

P05161.

GenomeRNAi

9636.

NextBio

36167.

SOURCE

Search...

Entry information

Entry name

ISG15_HUMAN

Accession

Primary (citable) accession number: P05161
Secondary accession number(s): Q5SVA4, Q7Z2G2, Q96GF0

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 13, 1987
Last sequence update:	January 23, 2007
Last modified:	May 1, 2013
This is version 150 of the entry and version 5 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.