SIVA_HUMAN
ID SIVA_HUMAN Reviewed; 175 AA.
AC O15304; Q96P98; Q9UPD6;
DT 23-MAY-2003, integrated into UniProtKB/Swiss-Prot.
DT 23-MAY-2003, sequence version 2.
DT 03-AUG-2022, entry version 173.
DE RecName: Full=Apoptosis regulatory protein Siva;
DE AltName: Full=CD27-binding protein;
DE Short=CD27BP;
GN Name=SIVA1; Synonyms=SIVA;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND INTERACTION WITH CD27.
RC TISSUE=Cervix carcinoma, and Thymus;
RX PubMed=9177220; DOI=10.1073/pnas.94.12.6346;
RA Prasad K.V.S., Ao Z., Yoon Y., Wu M.X., Rizk M., Jacquot S.,
RA Schlossman S.F.;
RT "CD27, a member of the tumor necrosis factor receptor family, induces
RT apoptosis and binds to Siva, a proapoptotic protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:6346-6351(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Ovary;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 164-175.
RC TISSUE=Monocytic leukemia;
RA Kang H.S., Park Y.J., Jung H.M., Jun D.Y., Huh T.L., Kim Y.H.;
RT "Characterization of TPA-responsive genes in U937 cells using ordered
RT differential display PCR.";
RL Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP INTERACTION WITH COXSACKIEVIRUS B3 VP2.
RX PubMed=10756043; DOI=10.1128/jvi.74.9.4284-4290.2000;
RA Henke A., Launhardt H., Klement K., Stelzner A., Zell R., Munder T.;
RT "Apoptosis in coxsackievirus B3-caused diseases: interaction between the
RT capsid protein VP2 and the proapoptotic protein siva.";
RL J. Virol. 74:4284-4290(2000).
RN [5]
RP PHOSPHORYLATION AT TYR-34, AND MUTAGENESIS OF TYR-34 AND TYR-53.
RX PubMed=11278261; DOI=10.1074/jbc.c100050200;
RA Cao C., Ren X., Kharbanda S., Koleske A., Prasad K.V.S., Kufe D.;
RT "The ARG tyrosine kinase interacts with Siva-1 in the apoptotic response to
RT oxidative stress.";
RL J. Biol. Chem. 276:11465-11468(2001).
RN [6]
RP INTERACTION WITH COXSACKIEVIRUS B3 VP2 (MICROBIAL INFECTION).
RX PubMed=11601913; DOI=10.1006/viro.2001.1082;
RA Henke A., Nestler M., Strunze S., Saluz H.-P., Hortschansky P., Menzel B.,
RA Martin U., Zell R., Stelzner A., Munder T.;
RT "The apoptotic capability of coxsackievirus B3 is influenced by the
RT efficient interaction between the capsid protein VP2 and the proapoptotic
RT host protein Siva.";
RL Virology 289:15-22(2001).
RN [7]
RP FUNCTION, AND INTERACTION WITH BCL2L1.
RX PubMed=12011449; DOI=10.1073/pnas.102182299;
RA Xue L., Chu F., Cheng Y., Sun X., Borthakur A., Ramarao M., Pandey P.,
RA Wu M., Schlossman S.F., Prasad K.V.S.;
RT "Siva-1 binds to and inhibits BCL-X(L)-mediated protection against UV
RT radiation-induced apoptosis.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:6925-6930(2002).
RN [8]
RP FUNCTION, AND INTERACTION WITH BCL2L1.
RX PubMed=14739602; DOI=10.1023/b:appt.0000012125.01799.4c;
RA Chu F., Borthakur A., Sun X., Barkinge J., Gudi R., Hawkins S.,
RA Prasad K.V.S.;
RT "The Siva-1 putative amphipathic helical region (SAH) is sufficient to bind
RT to BCL-XL and sensitize cells to UV radiation induced apoptosis.";
RL Apoptosis 9:83-95(2004).
RN [9]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=15034012; DOI=10.4049/jimmunol.172.7.4008;
RA Py B., Slomianny C., Auberger P., Petit P.X., Benichou S.;
RT "Siva-1 and an alternative splice form lacking the death domain, Siva-2,
RT similarly induce apoptosis in T lymphocytes via a caspase-dependent
RT mitochondrial pathway.";
RL J. Immunol. 172:4008-4017(2004).
RN [10]
RP FUNCTION, AND POSSIBLE PHARMACEUTICAL USE.
RX PubMed=15958577; DOI=10.1158/0008-5472.can-04-3270;
RA Chu F., Barkinge J., Hawkins S., Gudi R., Salgia R., Kanteti P.V.S.;
RT "Expression of Siva-1 protein or its putative amphipathic helical region
RT enhances cisplatin-induced apoptosis in breast cancer cells: effect of
RT elevated levels of BCL-2.";
RL Cancer Res. 65:5301-5309(2005).
RN [11]
RP ZINC-BINDING, AND INTERACTION WITH CD27 AND PXMP2.
RX PubMed=16683188; DOI=10.1007/s11010-005-9082-6;
RA Nestler M., Martin U., Hortschansky P., Saluz H.-P., Henke A., Munder T.;
RT "The zinc containing pro-apoptotic protein siva interacts with the
RT peroxisomal membrane protein pmp22.";
RL Mol. Cell. Biochem. 287:147-155(2006).
RN [12]
RP FUNCTION.
RX PubMed=16491128; DOI=10.1038/sj.onc.1209381;
RA Gudi R., Barkinge J., Hawkins S., Chu F., Manicassamy S., Sun Z.,
RA Duke-Cohan J.S., Prasad K.V.S.;
RT "Siva-1 negatively regulates NF-kappaB activity: effect on T-cell receptor-
RT mediated activation-induced cell death (AICD).";
RL Oncogene 25:3458-3462(2006).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-70, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
CC -!- FUNCTION: Induces CD27-mediated apoptosis. Inhibits BCL2L1 isoform Bcl-
CC x(L) anti-apoptotic activity. Inhibits activation of NF-kappa-B and
CC promotes T-cell receptor-mediated apoptosis.
CC {ECO:0000269|PubMed:12011449, ECO:0000269|PubMed:14739602,
CC ECO:0000269|PubMed:15034012, ECO:0000269|PubMed:15958577,
CC ECO:0000269|PubMed:16491128}.
CC -!- COFACTOR: [Isoform 1]:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000269|PubMed:16683188};
CC Note=Isoform 1 binds 3 Zn(2+) ions. {ECO:0000269|PubMed:16683188};
CC -!- COFACTOR: [Isoform 2]:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000269|PubMed:16683188};
CC Note=Isoform 2 binds 2 Zn(2+) ions. {ECO:0000269|PubMed:16683188};
CC -!- SUBUNIT: Binds through its N-terminal region to the C-terminus of CD27
CC and to PXMP2/PMP22. Binds to the C-terminus of TNFRSF18/GITR. Isoform 1
CC binds to BCL2L1/BCLX isoform Bcl-x(L) but not to BAX.
CC {ECO:0000269|PubMed:10756043, ECO:0000269|PubMed:11601913,
CC ECO:0000269|PubMed:12011449, ECO:0000269|PubMed:14739602,
CC ECO:0000269|PubMed:16683188, ECO:0000269|PubMed:9177220}.
CC -!- SUBUNIT: (Microbial infection) Interacts with coxsackievirus B3 capsid
CC protein VP2; this interaction inhibits the binding of SIVA1 to CD27.
CC {ECO:0000269|PubMed:11601913}.
CC -!- INTERACTION:
CC O15304; P10415: BCL2; NbExp=2; IntAct=EBI-520756, EBI-77694;
CC O15304; Q07817: BCL2L1; NbExp=2; IntAct=EBI-520756, EBI-78035;
CC O15304; Q07817-1: BCL2L1; NbExp=2; IntAct=EBI-520756, EBI-287195;
CC O15304; P26842: CD27; NbExp=3; IntAct=EBI-520756, EBI-520729;
CC O15304; Q9NR77: PXMP2; NbExp=3; IntAct=EBI-520756, EBI-1392944;
CC O15304; P03129: E7; Xeno; NbExp=4; IntAct=EBI-520756, EBI-866453;
CC O15304-1; Q07817-1: BCL2L1; NbExp=5; IntAct=EBI-520766, EBI-287195;
CC O15304-2; P29972: AQP1; NbExp=3; IntAct=EBI-12372219, EBI-745213;
CC O15304-2; Q2NKX9: C2orf68; NbExp=7; IntAct=EBI-12372219, EBI-11603468;
CC O15304-2; Q8NEC5: CATSPER1; NbExp=3; IntAct=EBI-12372219, EBI-744545;
CC O15304-2; Q02930-3: CREB5; NbExp=3; IntAct=EBI-12372219, EBI-10192698;
CC O15304-2; P49639: HOXA1; NbExp=3; IntAct=EBI-12372219, EBI-740785;
CC O15304-2; A0A0C4DG38: ING3; NbExp=3; IntAct=EBI-12372219, EBI-10263367;
CC O15304-2; Q6PEX3: KRTAP26-1; NbExp=3; IntAct=EBI-12372219, EBI-3957672;
CC O15304-2; Q96HA8: NTAQ1; NbExp=3; IntAct=EBI-12372219, EBI-741158;
CC O15304-2; Q8IYS1: PM20D2; NbExp=3; IntAct=EBI-12372219, EBI-11339910;
CC O15304-2; Q7Z6R9: TFAP2D; NbExp=3; IntAct=EBI-12372219, EBI-11952651;
CC O15304-2; Q9NWS9-2: ZNF446; NbExp=3; IntAct=EBI-12372219, EBI-740232;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15034012}. Nucleus
CC {ECO:0000269|PubMed:15034012}. Note=In the nucleus, accumulates in dot-
CC like structures.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=Siva-1;
CC IsoId=O15304-1; Sequence=Displayed;
CC Name=2; Synonyms=Siva-2;
CC IsoId=O15304-2; Sequence=VSP_007525;
CC -!- TISSUE SPECIFICITY: Ubiquitous. Mostly expressed in thymus, testis,
CC ovary, prostate, small intestine and spleen and less in colon.
CC -!- PTM: Phosphorylated by ABL2/ARG in response to oxidative stress.
CC {ECO:0000269|PubMed:11278261}.
CC -!- PHARMACEUTICAL: Could be used as a potentiator of cisplatin-based
CC chemotherapy. Enhances cisplatin-mediated apoptosis, even under
CC conditions where cisplatin resistance occurs due to elevated levels of
CC BCL2 or BCL2L1.
CC -!- MISCELLANEOUS: [Isoform 2]: Mouse isoform 2 has been shown
CC (PubMed:9177220) to have no pro-apoptotic activity. However, human
CC isoform 2 has been shown to be capable of inducing apoptosis
CC (PubMed:15034012). {ECO:0000305|PubMed:15034012,
CC ECO:0000305|PubMed:9177220}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC51372.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=AAD50057.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; U82938; AAC51372.1; ALT_INIT; mRNA.
DR EMBL; AF033111; AAD50057.1; ALT_INIT; mRNA.
DR EMBL; BC034562; AAH34562.1; -; mRNA.
DR EMBL; AF401214; AAL02171.1; -; mRNA.
DR EMBL; BK000018; DAA01049.1; -; Genomic_DNA.
DR CCDS; CCDS9992.1; -. [O15304-1]
DR CCDS; CCDS9993.1; -. [O15304-2]
DR RefSeq; NP_006418.2; NM_006427.3. [O15304-1]
DR RefSeq; NP_068355.1; NM_021709.2. [O15304-2]
DR AlphaFoldDB; O15304; -.
DR BioGRID; 115823; 49.
DR CORUM; O15304; -.
DR IntAct; O15304; 21.
DR MINT; O15304; -.
DR STRING; 9606.ENSP00000329213; -.
DR DrugBank; DB01593; Zinc.
DR DrugBank; DB14487; Zinc acetate.
DR DrugBank; DB14533; Zinc chloride.
DR DrugBank; DB14548; Zinc sulfate, unspecified form.
DR iPTMnet; O15304; -.
DR PhosphoSitePlus; O15304; -.
DR BioMuta; SIVA1; -.
DR EPD; O15304; -.
DR jPOST; O15304; -.
DR MassIVE; O15304; -.
DR MaxQB; O15304; -.
DR PaxDb; O15304; -.
DR PeptideAtlas; O15304; -.
DR PRIDE; O15304; -.
DR ProteomicsDB; 48572; -. [O15304-1]
DR ProteomicsDB; 48573; -. [O15304-2]
DR Antibodypedia; 28226; 324 antibodies from 28 providers.
DR DNASU; 10572; -.
DR Ensembl; ENST00000329967.11; ENSP00000329213.6; ENSG00000184990.13. [O15304-1]
DR Ensembl; ENST00000347067.9; ENSP00000329447.6; ENSG00000184990.13. [O15304-2]
DR GeneID; 10572; -.
DR KEGG; hsa:10572; -.
DR MANE-Select; ENST00000329967.11; ENSP00000329213.6; NM_006427.4; NP_006418.2.
DR UCSC; uc001yph.4; human. [O15304-1]
DR CTD; 10572; -.
DR DisGeNET; 10572; -.
DR GeneCards; SIVA1; -.
DR HGNC; HGNC:17712; SIVA1.
DR HPA; ENSG00000184990; Low tissue specificity.
DR MIM; 605567; gene.
DR neXtProt; NX_O15304; -.
DR OpenTargets; ENSG00000184990; -.
DR PharmGKB; PA162403351; -.
DR VEuPathDB; HostDB:ENSG00000184990; -.
DR eggNOG; ENOG502S2B7; Eukaryota.
DR GeneTree; ENSGT00390000004842; -.
DR HOGENOM; CLU_2170136_0_0_1; -.
DR InParanoid; O15304; -.
DR OMA; FRGAQAC; -.
DR OrthoDB; 1386185at2759; -.
DR PhylomeDB; O15304; -.
DR TreeFam; TF332962; -.
DR PathwayCommons; O15304; -.
DR SignaLink; O15304; -.
DR SIGNOR; O15304; -.
DR BioGRID-ORCS; 10572; 73 hits in 1080 CRISPR screens.
DR ChiTaRS; SIVA1; human.
DR GeneWiki; SIVA1; -.
DR GenomeRNAi; 10572; -.
DR Pharos; O15304; Tbio.
DR PRO; PR:O15304; -.
DR Proteomes; UP000005640; Chromosome 14.
DR RNAct; O15304; protein.
DR Bgee; ENSG00000184990; Expressed in endometrium epithelium and 194 other tissues.
DR ExpressionAtlas; O15304; baseline and differential.
DR Genevisible; O15304; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:HGNC-UCL.
DR GO; GO:0005739; C:mitochondrion; IDA:HGNC-UCL.
DR GO; GO:0005654; C:nucleoplasm; IDA:HGNC-UCL.
DR GO; GO:0005175; F:CD27 receptor binding; IPI:HGNC-UCL.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0005164; F:tumor necrosis factor receptor binding; IEA:Ensembl.
DR GO; GO:0001618; F:virus receptor activity; ISS:HGNC-UCL.
DR GO; GO:0008270; F:zinc ion binding; IDA:HGNC-UCL.
DR GO; GO:0006924; P:activation-induced cell death of T cells; IDA:HGNC-UCL.
DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; IDA:BHF-UCL.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; IDA:BHF-UCL.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IDA:HGNC-UCL.
DR GO; GO:1901030; P:positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway; IDA:BHF-UCL.
DR InterPro; IPR022773; Siva.
DR PANTHER; PTHR14365; PTHR14365; 1.
DR Pfam; PF05458; Siva; 1.
DR PIRSF; PIRSF038096; Siva_cd27_bd; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Apoptosis; Cytoplasm; Host-virus interaction;
KW Metal-binding; Nucleus; Pharmaceutical; Phosphoprotein; Reference proteome;
KW Zinc.
FT CHAIN 1..175
FT /note="Apoptosis regulatory protein Siva"
FT /id="PRO_0000097774"
FT REGION 36..55
FT /note="Interaction with BCL2L1 isoform Bcl-x(L) and
FT inhibition of BCL2L1 anti-apoptotic activity"
FT REGION 105..123
FT /note="Interaction with coxsackievirus B3 VP2"
FT MOD_RES 34
FT /note="Phosphotyrosine; by ABL2"
FT /evidence="ECO:0000269|PubMed:11278261"
FT MOD_RES 70
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT VAR_SEQ 40..104
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:9177220"
FT /id="VSP_007525"
FT MUTAGEN 34
FT /note="Y->F: Abolishes phosphorylation and apoptotic
FT activity."
FT /evidence="ECO:0000269|PubMed:11278261"
FT MUTAGEN 53
FT /note="Y->F: No effect on phosphorylation or apoptotic
FT activity."
FT /evidence="ECO:0000269|PubMed:11278261"
SQ SEQUENCE 175 AA; 18695 MW; DB62B7DF4E6B39B3 CRC64;
MPKRSCPFAD VAPLQLKVRV SQRELSRGVC AERYSQEVFE KTKRLLFLGA QAYLDHVWDE
GCAVVHLPES PKPGPTGAPR AARGQMLIGP DGRLIRSLGQ ASEADPSGVA SIACSSCVRA
VDGKAVCGQC ERALCGQCVR TCWGCGSVAC TLCGLVDCSD MYEKVLCTSC AMFET
