Reviewed, UniProtKB/Swiss-Prot O15304 (SIVA_HUMAN)

Names and origin

Protein names

Recommended name:
    Apoptosis regulatory protein Siva
Alternative name(s):
    CD27-binding protein
      Short name=CD27BP

Gene names

Name:	SIVA1
Synonyms:	SIVA

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	175 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Induces CD27-mediated apoptosis. Inhibits BCL2L1 isoform Bcl-x(L) anti-apoptotic activity. Inhibits activation of NF-kappa-B and promotes T-cell receptor-mediated apoptosis. Ref.7 Ref.8 Ref.9 Ref.10 Ref.12
Cofactor	Isoform 1 binds 3 zinc ions. Isoform 2 binds 2 zinc ions.
Subunit structure	Binds through its N-terminal region to the C-terminus of CD27 and to PXMP2/PMP22. Binds to the C-terminus of TNFRSF18/GITR. Isoform 1 binds to BCL2L1/BCLX isoform Bcl-x(L) but not to BAX. Binds to capsid protein VP2 from coxsackievirus B3. Binding of SIVA1 to CD27 can be blocked by VP2. Ref.7 Ref.8 Ref.1 Ref.4 Ref.6 Ref.11
Subcellular location	Cytoplasm. Nucleus. Note= In the nucleus, accumulates in dot-like structures. Ref.9
Tissue specificity	Ubiquitous. Mostly expressed in thymus, testis, ovary, prostate, small intestine and spleen and less in colon.
Post-translational modification	Phosphorylated by ABL2/ARG in response to oxidative stress. Ref.5
Pharmaceutical use	Could be used as a potentiator of cisplatin-based chemotherapy. Enhances cisplatin-mediated apoptosis, even under conditions where cisplatin resistance occurs due to elevated levels of BCL2 or BCL2L1.

Ontologies

Keywords
Biological process	Apoptosis Host-virus interaction
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing
Ligand	Metal-binding Zinc
PTM	Phosphoprotein
Technical term	Pharmaceutical
Gene Ontology (GO)
Biological process	induction of apoptosis Ref.1 Inferred from direct assay. Source: HGNC interspecies interaction between organisms Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytoplasm Inferred from electronic annotation. Source: InterPro nucleus Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	CD27 receptor binding Ref.1 Inferred from physical interaction. Source: HGNC viral receptor activity Inferred from sequence or structural similarity. Source: HGNC zinc ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
BCL2	P10415	1	EBI-520756,EBI-77694
BCL2L1	Q07817	1	EBI-520756,EBI-78035
BCL2L1	Q07817-1	1	EBI-520756,EBI-287195
BCL2L1	Q07817-1	3	EBI-520766,EBI-287195
CD27	P26842	3	EBI-520756,EBI-520729
PXMP2	Q9NR77	1	EBI-520756,EBI-1392944

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: O15304-1)

Also known as: Siva-1;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: O15304-2)

Also known as: Siva-2;

The sequence of this isoform differs from the canonical sequence as follows:
     40-104: Missing.

Notes: Mouse isoform 2 has been shown (PubMed:9177220) to have no pro-apoptotic activity. However, human isoform 2 has been shown to be capable of inducing apoptosis (PubMed:15034012).

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 175	175	Apoptosis regulatory protein Siva		PRO_0000097774
Regions
	Region	36 – 55	20	Interaction with BCL2L1 isoform Bcl-x(L) and inhibition of BCL2L1 anti-apoptotic activity
	Region	105 – 123	19	Interaction with coxsackievirus B3 VP2
Amino acid modifications
	Modified residue	34	1	Phosphotyrosine; by ABL2 Ref.5
Natural variations
	Alternative sequence	40 – 104	65	Missing in isoform 2.		VSP_007525
Experimental info
	Mutagenesis	34	1	Y → F: Abolishes phosphorylation and apoptotic activity Ref.5
	Mutagenesis	53	1	Y → F: No effect on phosphorylation or apoptotic activity Ref.5

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (Siva-1) [UniParc]. Last modified May 23, 2003. Version 2. Checksum: DB62B7DF4E6B39B3	FASTA	175	18,695
	10 20 30 40 50 60 MPKRSCPFAD VAPLQLKVRV SQRELSRGVC AERYSQEVFE KTKRLLFLGA QAYLDHVWDE 70 80 90 100 110 120 GCAVVHLPES PKPGPTGAPR AARGQMLIGP DGRLIRSLGQ ASEADPSGVA SIACSSCVRA 130 140 150 160 170 VDGKAVCGQC ERALCGQCVR TCWGCGSVAC TLCGLVDCSD MYEKVLCTSC AMFET
	Isoform 2 (Siva-2). Checksum: 6A802C0D5B5CE41E		110	11,778
	10 20 30 40 50 60 MPKRSCPFAD VAPLQLKVRV SQRELSRGVC AERYSQEVFD PSGVASIACS SCVRAVDGKA 70 80 90 100 110 VCGQCERALC GQCVRTCWGC GSVACTLCGL VDCSDMYEKV LCTSCAMFET

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"CD27, a member of the tumor necrosis factor receptor family, induces apoptosis and binds to Siva, a proapoptotic protein." Prasad K.V.S., Ao Z., Yoon Y., Wu M.X., Rizk M., Jacquot S., Schlossman S.F. Proc. Natl. Acad. Sci. U.S.A. 94:6346-6351(1997) [PubMed: 9177220] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), INTERACTION WITH CD27. Tissue: Cervix carcinoma and Thymus.
[2]	"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] (ISOFORM 2). Tissue: Ovary.
[3]	"Characterization of TPA-responsive genes in U937 cells using ordered differential display PCR." Kang H.S., Park Y.J., Jung H.M., Jun D.Y., Huh T.L., Kim Y.H. Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 164-175. Tissue: Monocytic leukemia.
[4]	"Apoptosis in coxsackievirus B3-caused diseases: interaction between the capsid protein VP2 and the proapoptotic protein siva." Henke A., Launhardt H., Klement K., Stelzner A., Zell R., Munder T. J. Virol. 74:4284-4290(2000) [PubMed: 10756043] [Abstract] Cited for: INTERACTION WITH COXSACKIEVIRUS B3 VP2.
[5]	"The ARG tyrosine kinase interacts with Siva-1 in the apoptotic response to oxidative stress." Cao C., Ren X., Kharbanda S., Koleske A., Prasad K.V.S., Kufe D. J. Biol. Chem. 276:11465-11468(2001) [PubMed: 11278261] [Abstract] Cited for: PHOSPHORYLATION AT TYR-34, MUTAGENESIS OF TYR-34 AND TYR-53.
[6]	"The apoptotic capability of coxsackievirus B3 is influenced by the efficient interaction between the capsid protein VP2 and the proapoptotic host protein Siva." Henke A., Nestler M., Strunze S., Saluz H.-P., Hortschansky P., Menzel B., Martin U., Zell R., Stelzner A., Munder T. Virology 289:15-22(2001) [PubMed: 11601913] [Abstract] Cited for: INTERACTION WITH COXSACKIEVIRUS B3 VP2.
[7]	"Siva-1 binds to and inhibits BCL-X(L)-mediated protection against UV radiation-induced apoptosis." Xue L., Chu F., Cheng Y., Sun X., Borthakur A., Ramarao M., Pandey P., Wu M., Schlossman S.F., Prasad K.V.S. Proc. Natl. Acad. Sci. U.S.A. 99:6925-6930(2002) [PubMed: 12011449] [Abstract] Cited for: FUNCTION, INTERACTION WITH BCL2L1.
[8]	"The Siva-1 putative amphipathic helical region (SAH) is sufficient to bind to BCL-XL and sensitize cells to UV radiation induced apoptosis." Chu F., Borthakur A., Sun X., Barkinge J., Gudi R., Hawkins S., Prasad K.V.S. Apoptosis 9:83-95(2004) [PubMed: 14739602] [Abstract] Cited for: FUNCTION, INTERACTION WITH BCL2L1.
[9]	"Siva-1 and an alternative splice form lacking the death domain, Siva-2, similarly induce apoptosis in T lymphocytes via a caspase-dependent mitochondrial pathway." Py B., Slomianny C., Auberger P., Petit P.X., Benichou S. J. Immunol. 172:4008-4017(2004) [PubMed: 15034012] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[10]	"Expression of Siva-1 protein or its putative amphipathic helical region enhances cisplatin-induced apoptosis in breast cancer cells: effect of elevated levels of BCL-2." Chu F., Barkinge J., Hawkins S., Gudi R., Salgia R., Kanteti P.V.S. Cancer Res. 65:5301-5309(2005) [PubMed: 15958577] [Abstract] Cited for: FUNCTION, POSSIBLE PHARMACEUTICAL USE.
[11]	"The zinc containing pro-apoptotic protein siva interacts with the peroxisomal membrane protein pmp22." Nestler M., Martin U., Hortschansky P., Saluz H.-P., Henke A., Munder T. Mol. Cell. Biochem. 287:147-155(2006) [PubMed: 16683188] [Abstract] Cited for: ZINC-BINDING, INTERACTION WITH CD27 AND PXMP2.
[12]	"Siva-1 negatively regulates NF-kappaB activity: effect on T-cell receptor-mediated activation-induced cell death (AICD)." Gudi R., Barkinge J., Hawkins S., Chu F., Manicassamy S., Sun Z., Duke-Cohan J.S., Prasad K.V.S. Oncogene 25:3458-3462(2006) [PubMed: 16491128] [Abstract] Cited for: FUNCTION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	U82938 mRNA. Translation: AAC51372.1. Different initiation. AF033111 mRNA. Translation: AAD50057.1. Different initiation. BC034562 mRNA. Translation: AAH34562.1. AF401214 mRNA. Translation: AAL02171.1. BK000018 Genomic DNA. Translation: DAA01049.1.
RefSeq	NP_006418.2. NP_068355.1.
UniGene	Hs.112058
3D structure databases
ModBase	Search...
Protein-protein interaction databases
IntAct	O15304. 6 interactions.
PTM databases
PhosphoSite	O15304.
Proteomic databases
PRIDE	O15304.
Genome annotation databases
Ensembl	ENSG00000184990. Homo sapiens. [Contig view]
GeneID	10572.
KEGG	hsa:10572.
Organism-specific databases
GeneCards	GC14P104291.
H-InvDB	HIX0012018.
HGNC	HGNC:17712. SIVA1.
MIM	605567. gene.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	O15304.
HOVERGEN	O15304.
Gene expression databases
ArrayExpress	O15304.
CleanEx	HS_SIVA1.
GermOnline	ENSG00000184990. Homo sapiens.
Family and domain databases
InterPro	IPR008842. Siva_cd27_bd. [Graphical view]
Pfam	PF05458. Siva. 1 hit. [Graphical view]
PIRSF	PIRSF038096. Siva_cd27_bd. 1 hit.
ProtoNet	Search...
Other Resources
NextBio	40121.
SOURCE	Search...

Entry information

Entry name

SIVA_HUMAN

Accession

Primary (citable) accession number: O15304
Secondary accession number(s): Q96P98, Q9UPD6

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 23, 2003
Last sequence update:	May 23, 2003
Last modified:	December 16, 2008
This is version 69 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)