Reviewed, UniProtKB/Swiss-Prot P05161 (UCRP_HUMAN)

Names and origin

Protein names

Recommended name:
    Interferon-induced 17 kDa protein
Cleaved into the following chain:
    1- Recommended name:
            Ubiquitin cross-reactive protein
                Short name=hUCRP
        Alternative name(s):
            Interferon-induced 15 kDa protein

Gene names

Name:	ISG15
Synonyms:	G1P2, UCRP

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › 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
Gene Ontology (GO)
Biological process	ISG15-protein conjugation Inferred from direct assay. Source: HGNC cell-cell signaling Non-traceable author statement. Source: UniProtKB interspecies interaction between organisms Inferred from electronic annotation. Source: UniProtKB-KW modification-dependent protein catabolic process Inferred from electronic annotation. Source: UniProtKB-KW response to virus Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytoplasm Non-traceable author statement. Source: UniProtKB extracellular space Non-traceable author statement. Source: UniProtKB
Molecular function	protein binding Non-traceable author statement. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ELF3	P78545	1	EBI-746466,EBI-1057285

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.10

Chain

2 – 165

164

Interferon-induced 17 kDa protein

PRO_0000035985

Chain

2 – 157

156

Ubiquitin cross-reactive protein

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: dbSNP rs1921. Ref.5 Ref.6 Ref.9

VAR_016181

Experimental info

Sequence conflict

35

1

K → N in AAA36128. Ref.2

Secondary structure

1

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165

Helix Strand Turn

Details...

Beta strand

4 – 12

9

Beta strand

14 – 18

5

Helix

25 – 36

12

Helix

40 – 42

3

Beta strand

43 – 48

6

Beta strand

56 – 58

3

Helix

61 – 63

3

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)
	P05161-1 [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: 3087979] [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: 3476954] [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: 3350799] [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: 16710414] [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: 15489334] [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: 2477469] [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: 2440890] [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: 1373138] [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: 7526157] [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: 8550581] [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: 2005397] [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: 7490683] [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: 11157743] [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: 11788588] [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: 15131269] [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: 16254333] [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: 16009940] [Abstract] Cited for: FUNCTION.
[22]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
+	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.

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	[»]

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29814N.

IntAct

P05161. 3 interactions.

STRING

P05161.

Proteomic databases

PeptideAtlas

P05161.

PRIDE

P05161.

Genome annotation databases

Ensembl

ENST00000379389; ENSP00000368699; ENSG00000187608; Homo sapiens. [Genome view]

GeneID

9636.

KEGG

hsa:9636.

UCSC

uc001acj.2. human.

Organism-specific databases

CTD

9636.

GeneCards

GC01P000938.

H-InvDB

HIX0000011.

HGNC

HGNC:4053. ISG15.

HPA

HPA004627.

MIM

147571. gene.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG12926.

HOGENOM

HBG283063.

HOVERGEN

P05161.

InParanoid

P05161.

OMA

FMNLRLR.

OrthoDB

EOG9HQH4X.

PhylomeDB

P05161.

Gene expression databases

ArrayExpress

P05161.

Bgee

P05161.

CleanEx

HS_ISG15.

Genevestigator

P05161.

GermOnline

ENSG00000187608. Homo sapiens.

Family and domain databases

InterPro

IPR000626. Ubiquitin.
IPR019956. Ubiquitin_subgroup.
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 Resources

NextBio

36167.

SOURCE

Search...

Entry information

Entry name

UCRP_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:	January 19, 2010
This is version 117 of the entry and version 5 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.