ID SNCAP_HUMAN Reviewed; 919 AA. AC Q9Y6H5; D3DSZ1; Q05BS1; Q1PSC2; Q49AC6; Q504U9; Q6L984; Q6L985; AC Q6L986; Q9HC59; DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot. DT 22-JUL-2008, sequence version 2. DT 25-JAN-2012, entry version 103. DE RecName: Full=Synphilin-1; DE Short=Sph1; DE AltName: Full=Alpha-synuclein-interacting protein; GN Name=SNCAIP; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INTERACTION WITH SNCA, RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND VARIANT ALA-44. RC TISSUE=Brain; RX MEDLINE=99251592; PubMed=10319874; DOI=10.1038/8820; RA Engelender S., Kaminsky Z., Guo X., Sharp A.H., Amaravi R.K., RA Kleiderlein J.J., Margolis R.L., Troncoso J.C., Lanahan A., RA Worley P.F., Dawson V.L., Dawson T.M., Ross C.A.; RT "Synphilin-1 associates with alpha-synuclein and promotes the RT formation of cytosolic inclusions."; RL Nat. Genet. 22:110-114(1999). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1). RX MEDLINE=20424790; PubMed=10967135; DOI=10.1007/s003350010123; RA Engelender S., Wanner T., Kleiderlein J.J., Wakabayashi K., Tsuji S., RA Takahashi H., Ashworth R., Margolis R.L., Ross C.A.; RT "Organization of the human synphilin-1 gene, a candidate for RT Parkinson's disease."; RL Mamm. Genome 11:763-766(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION, INTERACTION WITH RP SNCA, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=16595633; DOI=10.1073/pnas.0509707103; RA Eyal A., Szargel R., Avraham E., Liani E., Haskin J., Rott R., RA Engelender S.; RT "Synphilin-1A: an aggregation-prone isoform of synphilin-1 that causes RT neuronal death and is present in aggregates from alpha-synucleinopathy RT patients."; RL Proc. Natl. Acad. Sci. U.S.A. 103:5917-5922(2006). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 4 AND 6), AND VARIANT ALA-44. RC TISSUE=Cerebellum, and Testis; RA Lim M.K., Ohsawa Y., Kawamura T., Asakawa S., Takayanagi A., RA Minoshima S., Shimizu N.; RT "Identification and characterization of alternatively spliced form of RT human synphilin-1."; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2; 3 AND 5). RC TISSUE=Brain, and Testis; 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP INTERACTION WITH PARK2, AND UBIQUITINATION. RX MEDLINE=21474644; PubMed=11590439; DOI=10.1038/nm1001-1144; RA Chung K.K.K., Zhang Y., Lim K.L., Tanaka Y., Huang H., Gao J., RA Ross C.A., Dawson V.L., Dawson T.M.; RT "Parkin ubiquitinates the alpha-synuclein-interacting protein, RT synphilin-1: implications for Lewy-body formation in Parkinson RT disease."; RL Nat. Med. 7:1144-1150(2001). RN [8] RP INTERACTION WITH RNF19A, AND UBIQUITINATION. RX PubMed=12750386; DOI=10.1074/jbc.M302763200; RA Ito T., Niwa J., Hishikawa N., Ishigaki S., Doyu M., Sobue G.; RT "Dorfin localizes to Lewy bodies and ubiquitylates synphilin-1."; RL J. Biol. Chem. 278:29106-29114(2003). RN [9] RP INTERACTION WITH SIAH1, AND DEGRADATION. RX PubMed=14506261; DOI=10.1074/jbc.M306347200; RA Nagano Y., Yamashita H., Takahashi T., Kishida S., Nakamura T., RA Iseki E., Hattori N., Mizuno Y., Kikuchi A., Matsumoto M.; RT "Siah-1 facilitates ubiquitination and degradation of synphilin-1."; RL J. Biol. Chem. 278:51504-51514(2003). RN [10] RP SUBCELLULAR LOCATION, UBIQUITINATION, PROTEASOMAL DEGRADATION, RP INTERACTION WITH SIAH1 AND SIAH2, AND MUTAGENESIS OF VAL-79 AND RP PRO-81. RX PubMed=15064394; DOI=10.1073/pnas.0401081101; RA Liani E., Eyal A., Avraham E., Shemer R., Szargel R., Berg D., RA Bornemann A., Riess O., Ross C.A., Rott R., Engelender S.; RT "Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its RT presence in cellular inclusions and Lewy bodies imply a role in RT Parkinson's disease."; RL Proc. Natl. Acad. Sci. U.S.A. 101:5500-5505(2004). RN [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-387, AND MASS RP SPECTROMETRY. RC TISSUE=Cervix carcinoma; RX PubMed=18187866; DOI=10.2116/analsci.24.161; RA Imami K., Sugiyama N., Kyono Y., Tomita M., Ishihama Y.; RT "Automated phosphoproteome analysis for cultured cancer cells by two- RT dimensional nanoLC-MS using a calcined titania/C18 biphasic column."; RL Anal. Sci. 24:161-166(2008). RN [12] RP FUNCTION, AND INTERACTION WITH SIAH1. RX PubMed=19224863; DOI=10.1074/jbc.M805990200; RA Szargel R., Rott R., Eyal A., Haskin J., Shani V., Balan L., RA Wolosker H., Engelender S.; RT "Synphilin-1A inhibits seven in absentia homolog (SIAH) and modulates RT alpha-synuclein monoubiquitylation and inclusion formation."; RL J. Biol. Chem. 284:11706-11716(2009). RN [13] RP STRUCTURE BY NMR OF 512-557, INTERACTION WITH SNCA, PROMOTION OF RP INCLUSION BODY FORMATION, AND SUBCELLULAR LOCATION. RX PubMed=19762560; DOI=10.1096/fj.09-133082; RA Xie Y.Y., Zhou C.J., Zhou Z.R., Hong J., Che M.X., Fu Q.S., Song A.X., RA Lin D.H., Hu H.Y.; RT "Interaction with synphilin-1 promotes inclusion formation of alpha- RT synuclein: mechanistic insights and pathological implication."; RL FASEB J. 24:196-205(2010). RN [14] RP VARIANT CYS-621, CHARACTERIZATION OF VARIANT CYS-621, AND POSSIBLE RP INVOLVEMENT IN SUSCEPTIBILITY TO PARKINSON DISEASE. RX PubMed=12761037; DOI=10.1093/hmg/ddg134; RA Marx F.P., Holzmann C., Strauss K.M., Li L., Eberhardt O., RA Gerhardt E., Cookson M.R., Hernandez D., Farrer M.J., Kachergus J., RA Engelender S., Ross C.A., Berger K., Schols L., Schulz J.B., Riess O., RA Kruger R.; RT "Identification and functional characterization of a novel R621C RT mutation in the synphilin-1 gene in Parkinson's disease."; RL Hum. Mol. Genet. 12:1223-1231(2003). RN [15] RP VARIANTS ALA-44; CYS-621 AND GLN-706, AND LACK OF ASSOCIATION WITH RP PARKINSON DISEASE. RX PubMed=18366718; DOI=10.1186/1471-2350-9-19; RA Myhre R., Klungland H., Farrer M.J., Aasly J.O.; RT "Genetic association study of synphilin-1 in idiopathic Parkinson's RT disease."; RL BMC Med. Genet. 9:19-19(2008). CC -!- FUNCTION: Isoform 2 inhibits the ubiquitin ligase activity of CC SIAH1 and inhibits proteasomal degradation of target proteins. CC Isoform 2 inhibits autoubiquitination and proteasomal degradation CC of SIAH1, and thereby increases cellular levels of SIAH. Isoform 2 CC modulates SNCA monoubiquitination by SIAH1. CC -!- SUBUNIT: Homodimer (Probable). Heterodimer of isoform 1 and CC isoform 2 (Probable). Interacts with SIAH1, SIAH2, SNCA, RNF19A CC AND PARK2. Isoform 2 has a strong tendency to form aggregates and CC can sequester isoform 1. CC -!- SUBCELLULAR LOCATION: Cytoplasm. Note=Detected in cytoplasmic CC inclusion bodies, together with SNCA. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=6; CC Name=1; Synonyms=1a; CC IsoId=Q9Y6H5-1; Sequence=Displayed; CC Name=2; Synonyms=Synphilin-1A; CC IsoId=Q9Y6H5-2; Sequence=VSP_038839, VSP_038842, VSP_038845; CC Name=3; CC IsoId=Q9Y6H5-3; Sequence=VSP_038840, VSP_038845; CC Name=4; Synonyms=1b; CC IsoId=Q9Y6H5-4; Sequence=VSP_038841; CC Name=5; CC IsoId=Q9Y6H5-5; Sequence=VSP_038839, VSP_038842; CC Name=6; Synonyms=1c; CC IsoId=Q9Y6H5-6; Sequence=VSP_038840, VSP_038843, VSP_038844; CC -!- TISSUE SPECIFICITY: Detected in brain (at protein level). Widely CC expressed, with highest levels in brain, heart and placenta. CC -!- PTM: Ubiquitinated; mediated by SIAH1, SIAH2 or RNF19A and leading CC to its subsequent proteasomal degradation. In the absence of CC proteasomal degradation, ubiquitinated SNCAIP accumulates in CC cytoplasmic inclusion bodies. Isoform 2 is subject to limited CC ubiquitination that does not lead to proteasomal degradation. CC -!- DISEASE: Defects in SNCAIP may be a cause of Parkinson disease CC (PARK) [MIM:168600]. A complex neurodegenerative disorder CC characterized by bradykinesia, resting tremor, muscular rigidity CC and postural instability. Additional features are characteristic CC postural abnormalities, dysautonomia, dystonic cramps, and CC dementia. The pathology of Parkinson disease involves the loss of CC dopaminergic neurons in the substantia nigra and the presence of CC Lewy bodies (intraneuronal accumulations of aggregated proteins), CC in surviving neurons in various areas of the brain. The disease is CC progressive and usually manifests after the age of 50 years, CC although early-onset cases (before 50 years) are known. The CC majority of the cases are sporadic suggesting a multifactorial CC etiology based on environmental and genetic factors. However, some CC patients present with a positive family history for the disease. CC Familial forms of the disease usually begin at earlier ages and CC are associated with atypical clinical features. CC -!- MISCELLANEOUS: Constructs encoding portions of SNCA and SNCAIP co- CC transfected in mammalian cells promote cytosolic inclusions CC resembling the Lewy bodies of Parkinson disease. Coexpression of CC SNCA, SNCAIP, and PARK2 result in the formation of Lewy body-like. CC ubiquitin-positive cytosolic inclusions. SNCAIP isoform 2 is CC particularly aggregatation-prone. Familial mutations in PARK2 CC disrupt the ubiquitination of SNCAIP and the formation of the CC ubiquitin-positive inclusions. These results provide a molecular CC basis for the ubiquitination of Lewy body-associated proteins and CC link PARK2 and SNCA in a common pathogenic mechanism through their CC interaction with SNCAIP. CC -!- SIMILARITY: Contains 6 ANK repeats. CC -!- WEB RESOURCE: Name=GeneReviews; CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/SNCAIP"; CC ----------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution-NoDerivs License CC ----------------------------------------------------------------------- DR EMBL; AF076929; AAD30362.1; -; mRNA. DR EMBL; AF167306; AAG17478.1; -; Genomic_DNA. DR EMBL; AF167301; AAG17478.1; JOINED; Genomic_DNA. DR EMBL; AF167302; AAG17478.1; JOINED; Genomic_DNA. DR EMBL; AF167303; AAG17478.1; JOINED; Genomic_DNA. DR EMBL; AF167304; AAG17478.1; JOINED; Genomic_DNA. DR EMBL; AF167305; AAG17478.1; JOINED; Genomic_DNA. DR EMBL; DQ227317; ABB51162.1; -; mRNA. DR EMBL; CH471086; EAW48889.1; -; Genomic_DNA. DR EMBL; AB110788; BAD19017.1; -; mRNA. DR EMBL; AB110789; BAD19018.1; -; mRNA. DR EMBL; AB110790; BAD19019.1; -; mRNA. DR EMBL; CH471086; EAW48890.1; -; Genomic_DNA. DR EMBL; BC033743; AAH33743.1; -; mRNA. DR EMBL; BC040552; AAH40552.1; -; mRNA. DR EMBL; BC094759; AAH94759.1; -; mRNA. DR IPI; IPI00002293; -. DR IPI; IPI00385910; -. DR IPI; IPI00438113; -. DR IPI; IPI00956081; -. DR IPI; IPI00956102; -. DR IPI; IPI00967042; -. DR RefSeq; NP_001229864.1; NM_001242935.1. DR RefSeq; NP_005451.2; NM_005460.2. DR UniGene; Hs.426463; -. DR PDB; 2KES; NMR; -; A=512-557. DR PDBsum; 2KES; -. DR ProteinModelPortal; Q9Y6H5; -. DR SMR; Q9Y6H5; 280-557. DR IntAct; Q9Y6H5; 6. DR MINT; MINT-1380209; -. DR STRING; Q9Y6H5; -. DR PhosphoSite; Q9Y6H5; -. DR DMDM; 205831000; -. DR PRIDE; Q9Y6H5; -. DR Ensembl; ENST00000261367; ENSP00000261367; ENSG00000064692. DR Ensembl; ENST00000261368; ENSP00000261368; ENSG00000064692. DR Ensembl; ENST00000379533; ENSP00000368848; ENSG00000064692. DR Ensembl; ENST00000379536; ENSP00000368851; ENSG00000064692. DR Ensembl; ENST00000395469; ENSP00000378852; ENSG00000064692. DR Ensembl; ENST00000503116; ENSP00000423199; ENSG00000064692. DR GeneID; 9627; -. DR KEGG; hsa:9627; -. DR CTD; 9627; -. DR GeneCards; GC05P121675; -. DR HGNC; HGNC:11139; SNCAIP. DR HPA; HPA003266; -. DR MIM; 168600; phenotype. DR MIM; 603779; gene. DR neXtProt; NX_Q9Y6H5; -. DR PharmGKB; PA35987; -. DR GeneTree; ENSGT00390000001485; -. DR HOVERGEN; HBG061375; -. DR OMA; PIVESVE; -. DR PhylomeDB; Q9Y6H5; -. DR NextBio; 36127; -. DR PMAP-CutDB; Q9Y6H5; -. DR ArrayExpress; Q9Y6H5; -. DR Bgee; Q9Y6H5; -. DR CleanEx; HS_SNCAIP; -. DR Genevestigator; Q9Y6H5; -. DR GermOnline; ENSG00000064692; Homo sapiens. DR GO; GO:0005737; C:cytoplasm; IDA:MGI. DR GO; GO:0043025; C:neuronal cell body; NAS:UniProtKB. DR GO; GO:0005730; C:nucleolus; IDA:HPA. DR GO; GO:0042734; C:presynaptic membrane; NAS:UniProtKB. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB. DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW. DR GO; GO:0042417; P:dopamine metabolic process; IDA:MGI. DR GO; GO:0090083; P:regulation of inclusion body assembly; IDA:BHF-UCL. DR GO; GO:0046928; P:regulation of neurotransmitter secretion; IDA:MGI. DR InterPro; IPR002110; Ankyrin_rpt. DR InterPro; IPR020683; Ankyrin_rpt-contain_dom. DR Gene3D; G3DSA:1.25.40.20; ANK; 1. DR KO; K04558; -. DR Pfam; PF12796; Ank_2; 2. DR SMART; SM00248; ANK; 4. DR SUPFAM; SSF48403; ANK; 1. DR PROSITE; PS50297; ANK_REP_REGION; 1. DR PROSITE; PS50088; ANK_REPEAT; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ANK repeat; Coiled coil; KW Complete proteome; Cytoplasm; Neurodegeneration; Parkinson disease; KW Parkinsonism; Phosphoprotein; Polymorphism; Reference proteome; KW Repeat; Ubl conjugation. FT CHAIN 1 919 Synphilin-1. FT /FTId=PRO_0000067068. FT REPEAT 349 380 ANK 1. FT REPEAT 384 413 ANK 2. FT REPEAT 419 448 ANK 3. FT REPEAT 456 485 ANK 4. FT REPEAT 603 632 ANK 5. FT REPEAT 699 729 ANK 6. FT COILED 515 552 Potential. FT MOD_RES 387 387 Phosphothreonine. FT VAR_SEQ 1 366 Missing (in isoform 2 and isoform 5). FT /FTId=VSP_038839. FT VAR_SEQ 19 19 S -> SDNRSQGNRLQKLGLEDTDREDAMGFGSHRAKLTVV FT AALGACHCPENE (in isoform 3 and isoform FT 6). FT /FTId=VSP_038840. FT VAR_SEQ 335 394 Missing (in isoform 4). FT /FTId=VSP_038841. FT VAR_SEQ 367 394 QHLTSLMGEDCLNERNTEKLTPAGLAIK -> MTYLIQSHH FT SRRSQNCAEDVIRKTKTDQ (in isoform 2 and FT isoform 5). FT /FTId=VSP_038842. FT VAR_SEQ 476 541 LVEYGANVTMQNHAGEKPSQSAERQGHTLCSRYLVVVETCM FT SLASQVVKLTKQLKEQTVERVTLQN -> RLKIQGTWNGSE FT TCLFTHHFSSYPPISSGLQCQGQEGVLFIPDQVGAATNKQV FT LFQNQLPETKSSY (in isoform 6). FT /FTId=VSP_038843. FT VAR_SEQ 542 919 Missing (in isoform 6). FT /FTId=VSP_038844. FT VAR_SEQ 919 919 A -> EMYSSCINLSSNMLIEEHLCNDTRHNDINRKMKKSY FT SIKHIAEPESKELFL (in isoform 2 and isoform FT 3). FT /FTId=VSP_038845. FT VARIANT 44 44 V -> A (in dbSNP:rs56285021). FT /FTId=VAR_065358. FT VARIANT 235 235 E -> G (in dbSNP:rs6867105). FT /FTId=VAR_048312. FT VARIANT 621 621 R -> C (found in patients with symptoms FT of Parkinson disease; unknown FT pathological significance; reduced number FT of cytoplasmic inclusions in cells FT expressing C-621 compared with cells FT expressing wild-type (wt) protein when FT subjected to proteasomal inhibition; C- FT 621 transfected cells are more FT susceptible to staurosporine-induced cell FT death than cells expressin wt protein; FT dbSNP:rs28937592). FT /FTId=VAR_025667. FT VARIANT 706 706 E -> Q. FT /FTId=VAR_065359. FT MUTAGEN 79 79 V->N: Decreases interaction with SIAH1 FT and formation of cytoplasmic inclusion FT bodies; when associated with N-81. FT MUTAGEN 81 81 P->N: Decreases interaction with SIAH1 FT and formation of cytoplasmic inclusion FT bodies; when associated with N-79. FT CONFLICT 188 188 S -> F (in Ref. 6; AAH40552). FT CONFLICT 614 614 E -> G (in Ref. 6; AAH40552). FT CONFLICT 696 696 A -> G (in Ref. 6; AAH40552). FT CONFLICT 712 712 D -> G (in Ref. 6; AAH94759). FT CONFLICT 801 801 S -> P (in Ref. 6; AAH33743). FT CONFLICT 919 919 A -> E (in Ref. 6; AAH94759). FT HELIX 512 552 SQ SEQUENCE 919 AA; 100409 MW; 55C5316F250D0480 CRC64; MEAPEYLDLD EIDFSDDISY SVTSLKTIPE LCRRCDTQNE DRSVSSSSWN CGISTLITNT QKPTGIADVY SKFRPVKRVS PLKHQPETLE NNESDDQKNQ KVVEYQKGGE SDLGPQPQEL GPGDGVGGPP GKSSEPSTSL GELEHYDLDM DEILDVPYIK SSQQLASFTK VTSEKRILGL CTTINGLSGK ACSTGSSESS SSNMAPFCVL SPVKSPHLRK ASAVIHDQHK LSTEETEISP PLVKCGSAYE PENQSKDFLN KTFSDPHGRK VEKTTPDCQL RAFHLQSSAA ESKPEEQVSG LNRTSSQGPE ERSEYLKKVK SILNIVKEGQ ISLLPHLAAD NLDKIHDENG NNLLHIAASQ GHAECLQHLT SLMGEDCLNE RNTEKLTPAG LAIKNGQLEC VRWMVSETEA IAELSCSKDF PSLIHYAGCY GQEKILLWLL QFMQEQGISL DEVDQDGNSA VHVASQHGYL GCIQTLVEYG ANVTMQNHAG EKPSQSAERQ GHTLCSRYLV VVETCMSLAS QVVKLTKQLK EQTVERVTLQ NQLQQFLEAQ KSEGKSLPSS PSSPSSPASR KSQWKSPDAD DDSVAKSKPG VQEGIQVLGS LSASSRARPK AKDEDSDKIL RQLLGKEISE NVCTQEKLSL EFQDAQASSR NSKKIPLEKR ELKLARLRQL MQRSLSESDT DSNNSEDPKT TPVRKADRPR PQPIVESVES MDSAESLHLM IKKHTLASGG RRFPFSIKAS KSLDGHSPSP TSESSEPDLE SQYPGSGSIP PNQPSGDPQQ PSPDSTAAQK VATSPKSALK SPSSKRRTSQ NLKLRVTFEE PVVQMEQPSL ELNGEKDKDK GRTLQRTSTS NESGDQLKRP FGAFRSIMET LSGNQNNNNN YQAANQLKTS TLPLTSLGRK TDAKGNPASS ASKGKNKAA //