Q8K3Y6 (ZCCHV_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Zinc finger CCCH-type antiviral protein 1

Alternative name(s):
ADP-ribosyltransferase diphtheria toxin-like 13
Short name=ARTD13
Zinc finger antiviral protein
Short name=ZAP
Short name=rZAP

Gene names

Name:	Zc3hav1
Synonyms:	Zap

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	776 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Antiviral protein which inhibits the replication of viruses by recruiting the cellular RNA degradation machineries to degrade the viral mRNAs. Binds to a ZAP-responsive element (ZRE) present in the target viral mRNA, recruits cellular poly(A)-specific ribonuclease PARN to remove the poly(A) tail, and the 3'-5' exoribonuclease complex exosome to degrade the RNA body from the 3'-end. It also recruits the decapping complex DCP1-DCP2 through RNA helicase p72 (DDX17) to remove the cap structure of the viral mRNA to initiate its degradation from the 5'-end. Its target viruses belong to families which include retroviridae: human immunodeficiency virus type 1 (HIV-1) and moloney and murine leukemia virus (MoMLV), filoviridae: ebola virus (EBOV) and marburg virus (MARV), togaviridae: sindbis virus (SINV) and Ross river virus (RRV). Specifically targets the multiply spliced but not unspliced or singly spliced HIV-1 mRNAs for degradation. Ref.1 Ref.3 Ref.6 Ref.7 Ref.8 Ref.9 Ref.13
Subunit structure	Homodimer or homooligomer. Homooligomerization is essential for its antiviral activity. Interacts with EXOSC5. Interacts with EXOSC3, EXOSC7, DCP2 and DCP1A By similarity. Interacts with PARN in an RNA-independent manner By similarity. Interacts with XRN1 in an RNA-dependent manner By similarity. Interacts (via N-terminal domain) with DHX30 (via N-terminus) in an RNA-independent manner. Interacts (via N-terminal domain) with DDX17 in an RNA-independent manner. Ref.7 Ref.10 Ref.11 Ref.12 Ref.13 Ref.15
Subcellular location	Cytoplasm. Nucleus. Note: Localizes in the cytoplasm at steady state, but shuttles between nucleus and cytoplasm in a XPO1-dependent manner. Ref.4 Ref.8
Tissue specificity	Expressed in the kidney and liver. Ref.1
Induction	By type I interferon (IFN) and viruses. Ref.8
Domain	The N-terminal domain is sufficient to bind to viral RNAs and promote their degradation. The second and fourth zinc fingers are involved in binding to specific viral RNAs By similarity. Ref.15
Post-translational modification	Phosphorylation at Ser-274 is essential for sequential phosphorylation of Ser-270, Ser-266, Ser-262 and Ser-257 by GSK3-beta. Phosphorylation by GSK3-beta enhances its antiviral activity.
Sequence similarities	Contains 4 C3H1-type zinc fingers. Contains 1 WWE domain.

Ontologies

Keywords
Biological process	Antiviral defense Immunity Innate immunity
Cellular component	Cytoplasm Nucleus
Domain	Repeat Zinc-finger
Ligand	Metal-binding RNA-binding Zinc
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	defense response to virus Inferred from electronic annotation. Source: UniProtKB-KW innate immune response Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of viral genome replication Inferred from direct assay Ref.13. Source: UniProtKB positive regulation of mRNA catabolic process Inferred from direct assay Ref.7. Source: UniProtKB regulation of defense response to virus by host Inferred from direct assay Ref.1. Source: RGD response to virus Inferred from direct assay Ref.13. Source: UniProtKB
Cellular_component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	RNA binding Inferred from electronic annotation. Source: UniProtKB-KW zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 776

776

Zinc finger CCCH-type antiviral protein 1

PRO_0000211344

Regions

Domain

671 – 758

88

WWE

Zinc finger

73 – 86

14

C3H1-type 1

Zinc finger

88 – 110

23

C3H1-type 2

Zinc finger

150 – 172

23

C3H1-type 3

Zinc finger

169 – 193

25

C3H1-type 4

Region

1 – 254

254

N-terminal domain

Region

224 – 254

31

Binding to EXOSC5

Motif

69 – 76

8

Nuclear localization signal Ref.4

Motif

284 – 291

8

Nuclear export signal

Motif

405 – 406

2

Nuclear localization signal Potential

Compositional bias

343 – 348

6

Poly-Ser

Compositional bias

415 – 418

4

Poly-Leu

Compositional bias

533 – 536

4

Poly-Ser

Amino acid modifications

Modified residue

257

1

Phosphoserine; by GSK3-beta Ref.14

Modified residue

262

1

Phosphoserine; by GSK3-beta Ref.14

Modified residue

266

1

Phosphoserine; by GSK3-beta Ref.14

Modified residue

270

1

Phosphoserine; by GSK3-beta Ref.14

Modified residue

274

1

Phosphoserine Ref.14

Modified residue

283

1

Phosphoserine By similarity

Modified residue

325

1

Phosphoserine By similarity

Modified residue

351

1

Phosphoserine By similarity

Modified residue

398

1

Phosphoserine By similarity

Modified residue

501

1

Phosphotyrosine By similarity

Modified residue

544

1

Phosphoserine By similarity

Experimental info

Mutagenesis

88

1

C → R: Results in a non-functional protein with a dominant negative phenotype. Ref.11

Secondary structure

1

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776

Helix Strand Turn

Details...

Helix

9 – 16

8

Turn

17 – 19

3

Beta strand

20 – 22

3

Helix

23 – 30

8

Helix

34 – 44

11

Turn

46 – 48

3

Beta strand

49 – 53

5

Beta strand

62 – 66

5

Helix

89 – 92

4

Helix

97 – 99

3

Helix

115 – 123

9

Helix

131 – 139

9

Helix

143 – 145

3

Beta strand

156 – 158

3

Beta strand

163 – 166

4

Helix

175 – 178

4

Helix

196 – 205

10

Helix

209 – 223

15

Sequences

	Sequence		Length	Mass (Da)
	Q8K3Y6 [UniParc]. Last modified October 1, 2002. Version 1. Checksum: D13F61A9F8E5B552	FASTA	776	86,771
	10 20 30 40 50 60 MADPGVCCFI TKILCAHGGR MTLEELLGEI RLPEAQLYEL LETAGPDRFV LLETGGQAGI 70 80 90 100 110 120 TRSVVATTRA RVCRRKYCQR PCDSLHLCKL NLLGRCHYAQ SQRNLCKYSH DVLSEQNFQI 130 140 150 160 170 180 LKNHELSGLN QEELACLLVQ SDPFFLPEIC KSYKGEGRKQ TCGQPQPCER LHICEHFTRG 190 200 210 220 230 240 NCSYLNCLRS HNLMDRKVLT IMREHGLSPD VVQNIQDICN NKHARRNPPG TRAAHPHRRG 250 260 270 280 290 300 GAHRDRSKSR DRFLHNSLEF LSPVVSPLGS GPPSPDVTSC KDSLEDVSVD VTQKFKYLGT 310 320 330 340 350 360 HDRAQLSPVS SKAAGVQGPS QMRASQEFSE DGNLDDIFSR NRSDSSSSRA SAAKVAQRNE 370 380 390 400 410 420 AVAMKMGMEV KGKKEAPDID RVPFLNSYID GVTMEKASVS GIPGKKFTAN DLENLLLLND 430 440 450 460 470 480 TWKNVAKPQD LQTTGRITDS GQDKAFLQNK YGGNPVWASA STHNAPNGSS QIMDETPNVS 490 500 510 520 530 540 KSSTSGFAIK PAIAGGKEAV YSGVQSPRSQ VLAVPGEATT PVQSNRLPQS PLSSSSHRAA 550 560 570 580 590 600 ASGSPGKNST HTSVSPAIES SRMTSDPDEY LLRYILNPLF RMDNHGPKEI CQDHLYKGCQ 610 620 630 640 650 660 QSHCDRSHFH LPYRWQMFVY TTWRDFQDME SIEQAYCDPH VELILIENHQ INFQKMTCDS 670 680 690 700 710 720 YPIRRLSTPS YEEKPLSAVF ATKWIWYWKN EFNEYIQYGN ESPGHTSSDI NSAYLESFFQ 730 740 750 760 770 SCPRGVLPFQ AGSQKYELSF QGMIQTNIAS KTQRHVVRRP VFVSSNDVEQ KRRGPE

References

[1]	"Inhibition of retroviral RNA production by ZAP, a CCCH-type zinc finger protein." Gao G., Guo X., Goff S.P. Science 297:1703-1706(2002) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY.
[2]	Lubec G., Kang S.U., Lubec S. Submitted (SEP-2007) to UniProtKB Cited for: PROTEIN SEQUENCE OF 227-238; 341-349; 359-371 AND 548-562, MASS SPECTROMETRY. Strain: Sprague-Dawley. Tissue: Brain.
[3]	"Expression of the zinc-finger antiviral protein inhibits alphavirus replication." Bick M.J., Carroll J.W., Gao G., Goff S.P., Rice C.M., McDonald M.R. J. Virol. 77:11555-11562(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[4]	"ZAP is a CRM1-dependent nucleocytoplasmic shuttling protein." Liu L., Chen G., Ji X., Gao G. Biochem. Biophys. Res. Commun. 321:517-523(2004) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, NUCLEAR LOCALIZATION SIGNAL, NUCLEAR EXPORT SIGNAL.
[5]	"The zinc finger antiviral protein directly binds to specific viral mRNAs through the CCCH zinc finger motifs." Guo X., Carroll J.-W., McDonald M.R., Goff S.P., Gao G. J. Virol. 78:12781-12787(2004) [PubMed] [Europe PMC] [Abstract] Cited for: RNA-BINDING.
[6]	"Inhibition of filovirus replication by the zinc finger antiviral protein." Mueller S., Moeller P., Bick M.J., Wurr S., Becker S., Guenther S., Kuemmerer B.M. J. Virol. 81:2391-2400(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[7]	"The zinc-finger antiviral protein recruits the RNA processing exosome to degrade the target mRNA." Guo X., Ma J., Sun J., Gao G. Proc. Natl. Acad. Sci. U.S.A. 104:151-156(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH EXOSC5.
[8]	"The zinc finger antiviral protein acts synergistically with an interferon-induced factor for maximal activity against alphaviruses." MacDonald M.R., Machlin E.S., Albin O.R., Levy D.E. J. Virol. 81:13509-13518(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INDUCTION, SUBCELLULAR LOCATION.
[9]	"Positive selection and increased antiviral activity associated with the PARP-containing isoform of human zinc-finger antiviral protein." Kerns J.A., Emerman M., Malik H.S. PLoS Genet. 4:E21-E21(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[10]	"p72 DEAD box RNA helicase is required for optimal function of the zinc-finger antiviral protein." Chen G., Guo X., Lv F., Xu Y., Gao G. Proc. Natl. Acad. Sci. U.S.A. 105:4352-4357(2008) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH DDX17.
[11]	"Identification of a dominant negative inhibitor of human zinc finger antiviral protein reveals a functional endogenous pool and critical homotypic interactions." Law L.M., Albin O.R., Carroll J.W., Jones C.T., Rice C.M., Macdonald M.R. J. Virol. 84:4504-4512(2010) [PubMed] [Europe PMC] [Abstract] Cited for: SUBUNIT, MUTAGENESIS OF CYS-88.
[12]	"DEXH-Box protein DHX30 is required for optimal function of the zinc-finger antiviral protein." Ye P., Liu S., Zhu Y., Chen G., Gao G. Protein Cell 1:956-964(2010) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH DHX30.
[13]	"Zinc-finger antiviral protein inhibits HIV-1 infection by selectively targeting multiply spliced viral mRNAs for degradation." Zhu Y., Chen G., Lv F., Wang X., Ji X., Xu Y., Sun J., Wu L., Zheng Y.T., Gao G. Proc. Natl. Acad. Sci. U.S.A. 108:15834-15839(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH EXOSC5.
[14]	"Glycogen synthase kinase 3? (GSK3?) modulates antiviral activity of zinc-finger antiviral protein (ZAP)." Sun L., Lv F., Guo X., Gao G. J. Biol. Chem. 287:22882-22888(2012) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-257; SER-262; SER-266; SER-270 AND SER-274.
[15]	"Structure of N-terminal domain of ZAP indicates how a zinc-finger protein recognizes complex RNA." Chen S., Xu Y., Zhang K., Wang X., Sun J., Gao G., Liu Y. Nat. Struct. Mol. Biol. 19:430-435(2012) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 1-225, SUBUNIT, RNA-BINDING, DOMAIN N-TERMINAL.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF521008 mRNA. Translation: AAM75358.1.

IPI

IPI00202734.

UniGene

Rn.42053.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3U9G	X-ray	1.80	A	1-225	[»]

ProteinModelPortal

Q8K3Y6.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29842N.

PTM databases

PhosphoSite

Q8K3Y6.

Proteomic databases

PaxDb

Q8K3Y6.

PRIDE

Q8K3Y6.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

UCSC

RGD:628694. rat.

Organism-specific databases

RGD

628694. Zc3hav1.

Phylogenomic databases

eggNOG

NOG83866.

HOGENOM

HOG000236279.

HOVERGEN

HBG050384.

InParanoid

Q8K3Y6.

OrthoDB

EOG4HHP1P.

Gene expression databases

ArrayExpress

Q8K3Y6.

Genevestigator

Q8K3Y6.

Family and domain databases

InterPro

IPR004170. WWE-dom.
IPR000571. Znf_CCCH.
[Graphical view]

PROSITE

PS50918. WWE. 1 hit.
PS50103. ZF_C3H1. 2 hits.
[Graphical view]

ProtoNet

Search...

Entry information

Entry name

ZCCHV_RAT

Accession

Primary (citable) accession number: Q8K3Y6

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 10, 2004
Last sequence update:	October 1, 2002
Last modified:	April 3, 2013
This is version 65 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program