Reviewed, UniProtKB/Swiss-Prot P37840 (SYUA_HUMAN)

Names and origin

Protein names

Recommended name:
    Alpha-synuclein
Alternative name(s):
    Non-A beta component of AD amyloid
    Non-A4 component of amyloid precursor
      Short name(s)=NACP

Gene names

Name:	SNCA
Synonyms:	NACP, PARK1

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

General annotation (Comments)

Function	May be involved in the regulation of dopamine release and transport. Soluble protein, normally localized primarily at the presynaptic region of axons, which can form filamentous aggregates that are the major non amyloid component of intracellular inclusions in several neurodegenerative diseases (synucleinopathies). Induces fibrillization of microtubule-associated protein tau. Reduces neuronal responsiveness to various apoptotic stimuli, leading to a decreased caspase 3 activation.
Subunit structure	Soluble monomer which can form filamentous aggregates. Interacts with UCHL1 By similarity. Interacts with phospholipase D and histones.
Subcellular location	Cytoplasm. Membrane. Nucleus. Note= Membrane-bound in dopaminergic neurons. Also found in the nucleus.
Tissue specificity	Expressed principally in brain but is also expressed in low concentrations in all tissues examined except in liver. Concentrated in presynaptic nerve terminals.
Domain	The NAC domain is involved in the fibril formation. The middle region forms the core of the filaments. The C-terminus may regulate aggregation and determine the diameter of the filaments.
Post-translational modification	Phosphorylated, predominantly on serine residues. Phosphorylation by CK1 appears to occur on residues distinct from the residue phosphorylated by other kinases. Phosphorylation of Ser-129 is selective and extensive in synucleinopathy lesions. In vitro, phosphorylation at Ser-129 promoted insoluble fibril formation. Phosphorylated on Tyr-125 by a PTK2B-dependent pathway upon osmotic stress. Hallmark lesions of neurodegenerative synucleinopathies contain alpha-synuclein that is modified by nitration of tyrosine residues and possibly by dityrosine cross-linking to generated stable oligomers. Ubiquitinated. The predominant conjugate is the diubiquitinated form By similarity.
Involvement in disease	Defects in SNCA are a cause of autosomal dominant Parkinson disease 1 (PARK1) [MIM:168601, 168600]. Parkinson disease (PD) is a complex, multifactorial disorder that typically manifests after the age of 50 years, although early-onset cases (before 50 years) are known. PD generally arises as a sporadic condition but is occasionally inherited as a simple mendelian trait. Although sporadic and familial PD are very similar, inherited forms of the disease usually begin at earlier ages and are associated with atypical clinical features. PD is characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. Defects in SNCA are the cause of Parkinson disease 4 (PARK4) [MIM:605543, 168600]. Defects in SNCA are the cause of Lewy body dementia (DLB) [MIM:127750]. DLB is a neurodegenerative disorder clinically characterized by dementia and parkinsonism, often with fluctuating cognitive function, visual hallucinations, falls, syncopal episodes, and sensitivity to neuroleptic medication. Presence of Lewy bodies are the only essential pathologic features. Deposition of fibrillar amyloid proteins intraneuronally as neurofibrillary tangles is characteristic of Alzheimer disease (AD). SNCA is a minor protein found within these deposits, but a major non amyloid component. Brain iron accumulation type 1 (NBIA1, also called Hallervorden-Spatz syndrome), a rare neuroaxonal dystrophy, is histologically characterized by axonal spheroids, iron deposition, Lewy body (LB)-like intraneuronal inclusions, glial inclusions and neurofibrillary tangles. SNCA is found in LB-like inclusions, glial inclusions and spheroids.
Sequence similarities	Belongs to the synuclein family.

Ontologies

Keywords
Cellular component	Cytoplasm Membrane Nucleus
Coding sequence diversity	Alternative splicing
Disease	Alzheimer disease Amyloid Disease mutation Parkinson disease
Domain	Repeat
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	anti-apoptosis Traceable author statement. Source: ProtInc central nervous system development Ref.17 Traceable author statement. Source: ProtInc
Cellular component	cytoplasm Ref.1 Traceable author statement. Source: ProtInc
Molecular function	protein binding Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Notes: Additional isoforms seem to exist.

Isoform 1 (identifier: P37840-1)

Also known as: NACP140;

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 2-4 (identifier: P37840-2)

Also known as: NACP112;

The sequence of this isoform differs from the canonical sequence as follows:
     103-130: Missing.

Isoform 2-5 (identifier: P37840-3)

The sequence of this isoform differs from the canonical sequence as follows:
     41-54: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Molecule processing

Chain

1 – 140

140

Alpha-synuclein

Regions

Repeat

20 – 30

11

1

Repeat

31 – 41

11

2

Repeat

42 – 56

15

3; approximate

Repeat

57 – 67

11

4

Region

20 – 67

48

4 X 11 AA tandem repeats of [EGS]-K-T-K-[EQ]-[GQ]-V-X(4)

Amino acid modifications

Modified residue

87

1

Phosphoserine; by CK2

Modified residue

125

1

Phosphotyrosine

Modified residue

129

1

Phosphoserine; by BARK1, CK2 and GRK5

Natural variations

Alternative sequence

41 – 54

14

Missing in isoform 2-5.

Alternative sequence

103 – 130

28

Missing in isoform 2-4.

Natural variant

30

1

A → P in PARK1.

Natural variant

46

1

E → K in PARK1 and DLB; significant increase in binding to negatively charged phospholipid liposomes.

Natural variant

53

1

A → T in PARK1; no effect on osmotic stress-induced phosphorylation.

Experimental info

Mutagenesis

39

1

Y → F: No effect on osmotic stress-induced phosphorylation

Mutagenesis

125

1

Y → F: Abolishes osmotic stress-induced phosphorylation

Mutagenesis

133

1

Y → F: No effect on osmotic stress-induced phosphorylation

Mutagenesis

136

1

Y → F: No effect on osmotic stress-induced phosphorylation

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

140

Helix Strand Turn

Details...

Helix

3 – 37

35

Helix

45 – 92

48

Beta strand

110 – 113

4

Turn

120 – 122

3

Turn

124 – 126

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (NACP140) [UniParc]. Last modified October 1, 1994. Version 1. Checksum: 6BB2F12128931663	FASTA	140	14,460
	10 20 30 40 50 60 MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVATVAEKTK 70 80 90 100 110 120 EQVTNVGGAV VTGVTAVAQK TVEGAGSIAA ATGFVKKDQL GKNEEGAPQE GILEDMPVDP 130 140 DNEAYEMPSE EGYQDYEPEA
	Isoform 2-4 (NACP112) [UniParc]. Checksum: 16EA234777EFA89E		112	11,372
	10 20 30 40 50 60 MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVATVAEKTK 70 80 90 100 110 EQVTNVGGAV VTGVTAVAQK TVEGAGSIAA ATGFVKKDQL GKEGYQDYEP EA
	Isoform 2-5 [UniParc]. Checksum: 0F87D9A60E831E02		126	13,109
	10 20 30 40 50 60 MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV VAEKTKEQVT NVGGAVVTGV 70 80 90 100 110 120 TAVAQKTVEG AGSIAAATGF VKKDQLGKNE EGAPQEGILE DMPVDPDNEA YEMPSEEGYQ DYEPEA

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease." Ueda K., Fukushima H., Masliah E., Xia Y., Iwai A., Yoshimoto M., Otero D.A., Kondo J., Ihara Y., Saitoh T. Proc. Natl. Acad. Sci. U.S.A. 90:11282-11286(1993) [PubMed: 8248242] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 61-95. Tissue: Brain.
[2]	"The NACP/synuclein gene: chromosomal assignment and screening for alterations in Alzheimer disease." Campion D., Martin C., Heilig R., Charbonnier F., Moreau V., Flaman J.-M., Petit J.-L., Hannequin D., Brice A., Frebourg T. Genomics 26:254-257(1995) [PubMed: 7601450] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2-4 AND 2-5).
[3]	"Tissue-dependent alternative splicing of mRNA for NACP, the precursor of non-A beta component of Alzheimer's disease amyloid." Ueda K., Saitoh T., Mori H. Biochem. Biophys. Res. Commun. 205:1366-1372(1994) [PubMed: 7802671] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2-4). Tissue: Brain.
[4]	Xia Y., Silva R.D., Chen X.H., Saitoh T. Submitted (JAN-1996) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE.
[5]	"Human and mouse alpha-synuclein genes: comparative genomic sequence analysis and identification of a novel gene regulatory element." Touchman J.W., Dehejia A., Chiba-Falek O., Cabin D.E., Schwartz J.R., Orrison B.M., Polymeropoulos M.H., Nussbaum R.L. Genome Res. 11:78-86(2001) [PubMed: 11156617] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1 AND 2-4).
[6]	Hu X., Xu Y., Peng X., Yuan J., Qiang B. Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE (ISOFORM 1).
[7]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B. Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[8]	"NIEHS-SNPs, environmental genome project, NIEHS ES15478, Department of Genome Sciences, Seattle, WA (URL: http://egp.gs.washington.edu)." Livingston R.J., Rieder M.J., Shaffer T., Bertucci C., Baier C.N., Rajkumar N., Willa H.T., Daniels M., Downing T.K., Stanaway I.B., Nguyen C.P., Gildersleeve H., Cassidy C.M., Johnson E.J., Swanson J.E., McFarland I., Yool B., Park C., Nickerson D.A. Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [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] (ISOFORM 1). Tissue: Uterus.
[10]	"Constitutive phosphorylation of the Parkinson's disease associated alpha-synuclein." Okochi M., Walter J., Koyama A., Nakajo S., Baba M., Iwatsubo T., Meijer L., Kahle P.J., Haass C. J. Biol. Chem. 275:390-397(2000) [PubMed: 10617630] [Abstract] Cited for: PHOSPHORYLATION BY CASEIN KINASE.
[11]	"Synucleins are a novel class of substrates for G protein-coupled receptor kinases." Pronin A.N., Morris A.J., Surguchov A., Benovic J.L. J. Biol. Chem. 275:26515-26522(2000) [PubMed: 10852916] [Abstract] Cited for: PHOSPHORYLATION BY G-PROTEIN COUPLED RECEPTOR KINASE.
[12]	"Alpha-synuclein interacts with phospholipase D isozymes and inhibits pervanadate-induced phospholipase D activation in human embryonic kidney-293 cells." Ahn B.H., Rhim H., Kim S.Y., Sung Y.M., Lee M.Y., Choi J.Y., Wolozin B., Chang J.S., Lee Y.H., Kwon T.K., Chung K.C., Yoon S.H., Hahn S.J., Kim M.S., Jo Y.H., Min do S. J. Biol. Chem. 277:12334-12342(2002) [PubMed: 11821392] [Abstract] Cited for: INTERACTION WITH PHOSPHOLIPASE D.
[13]	"Nuclear localization of alpha-synuclein and its interaction with histones." Goers J., Manning-Bog A.B., McCormack A.L., Millett I.S., Doniach S., Di Monte D.A., Uversky V.N., Fink A.L. Biochemistry 42:8465-8471(2003) [PubMed: 12859192] [Abstract] Cited for: INTERACTION WITH HISTONES, SUBCELLULAR LOCATION.
[14]	"Role of alpha-synuclein carboxy-terminus on fibril formation in vitro." Murray I.V., Giasson B.I., Quinn S.M., Koppaka V., Axelsen P.H., Ischiropoulos H., Trojanowski J.Q., Lee V.M. Biochemistry 42:8530-8540(2003) [PubMed: 12859200] [Abstract] Cited for: ROLE OF THE C-TERMINUS IN FIBRILLOGENESIS.
[15]	"Recent advances on alpha-synuclein cell biology: functions and dysfunctions." Alves da Costa C. Curr. Mol. Med. 3:17-24(2003) [PubMed: 12558071] [Abstract] Cited for: REVIEW.
[16]	"Identification and characterization of a novel Pyk2/related adhesion focal tyrosine kinase-associated protein that inhibits alpha-synuclein phosphorylation." Takahashi T., Yamashita H., Nagano Y., Nakamura T., Ohmori H., Avraham H., Avraham S., Yasuda M., Matsumoto M. J. Biol. Chem. 278:42225-42233(2003) [PubMed: 12893833] [Abstract] Cited for: MUTAGENESIS OF TYR-39; TYR-125; TYR-133 AND TYR-136, CHARACTERIZATION OF VARIANT THR-53, PHOSPHORYLATION AT TYR-125.
[17]	"Mutation in the alpha-synuclein gene identified in families with Parkinson's disease." Polymeropoulos M.H., Lavedan C., Leroy E., Ide S.E., Dehejia A., Dutra A., Pike B., Root H., Rubenstein J., Boyer R., Stenroos E.S., Chandrasekharappa S., Athanassiadou A., Papapetropoulos T., Johnson W.G., Lazzarini A.M., Duvoisin R.C., di Iorio G., Golbe L.I., Nussbaum R.L. Science 276:2045-2047(1997) [PubMed: 9197268] [Abstract] Cited for: VARIANT PARK1 THR-53.
[18]	"Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease." Krueger R., Kuhn W., Mueller T., Woitalla D., Graeber M., Koesel S., Przuntek H., Epplen J.T., Schoels L., Riess O. Nat. Genet. 18:106-108(1998) [PubMed: 9462735] [Abstract] Cited for: VARIANT PARK1 PRO-30.
[19]	"The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia." Zarranz J.J., Alegre J., Gomez-Esteban J.C., Lezcano E., Ros R., Ampuero I., Vidal L., Hoenicka J., Rodriguez O., Atares B., Llorens V., Gomez Tortosa E., del Ser T., Munoz D.G., de Yebenes J.G. Ann. Neurol. 55:164-173(2004) [PubMed: 14755719] [Abstract] Cited for: VARIANT PARK1/DLB LYS-46.
[20]	"Mutation E46K increases phospholipid binding and assembly into filaments of human alpha-synuclein." Choi W., Zibaee S., Jakes R., Serpell L.C., Davletov B., Crowther R.A., Goedert M. FEBS Lett. 576:363-368(2004) [PubMed: 15498564] [Abstract] Cited for: CHARACTERIZATION OF VARIANT LYS-46.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBLGenBankDDBJ

L08850 mRNA. Translation: AAA16117.1.
L36674 mRNA. Translation: AAA98493.1.
L36675 mRNA. Translation: AAA98487.1.
D31839 mRNA. Translation: BAA06625.1.
U46901 , U46897, U46898, U46899 Genomic DNA. Translation: AAC02114.1.
AF163864 Genomic DNA. Translation: AAG30302.1.
AF163864 Genomic DNA. Translation: AAG30303.1.
AY049786 mRNA. Translation: AAL15443.1.
CR457058 mRNA. Translation: CAG33339.1.
DQ088379 Genomic DNA. Translation: AAY88735.1.
BC013293 mRNA. Translation: AAH13293.1.
BC108275 mRNA. Translation: AAI08276.1.

PIR

A49669.
S56746.

RefSeq

NP_000336.1.
NP_009292.1.

UniGene

Hs.271771

3D structure databases

PDBMSD

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1XQ8	NMR	-	A	1-140	[»]

DisProt

DP00070.

ModBase

Search...

Protein-protein interaction databases

IntAct

P37840.

PTM databases

PhosphoSite

P37840.

Polymorphism databases

NIEHS-SNPs

Search...

Genome annotation databases

Ensembl

ENSG00000145335. Homo sapiens. [Contig view]

GeneID

6622.

KEGG

hsa:6622.

Organism-specific databases

H-InvDB

HIX0004376.

HGNC

HGNC:11138. SNCA.

MIM

127750. phenotype.
163890. gene.
168600. phenotype.
168601. phenotype.
605543. phenotype.

Orphanet

1648. Lewy body dementia.
2828. Parkinson disease, genetic types.
33540. Parkinson's disease dementia, familial.

PharmGKB

PA35986.

GenAtlas

Search...

GeneCards

Search...

GeneLynx

Search...

Phylogenomic databases

HOGENOM

P37840.

HOVERGEN

P37840.

Gene expression databases

ArrayExpress

P37840.

CleanEx

HS_SNCA.

GermOnline

ENSG00000145335. Homo sapiens.

Family and domain databases

InterPro

IPR001058. Synuclein.
IPR002460. Synuclein_alpha.
[Graphical view]

Gene3D

G3DSA:1.10.287.700. Synuclein. 1 hit.

PANTHER

PTHR13820. Synuclein. 1 hit.

Pfam

PF01387. Synuclein. 1 hit.
[Graphical view]

PRINTS

PR01212. ASYNUCLEIN.
PR01211. SYNUCLEIN.

ProDom

PD010631. Synuclein. 1 hit.
[Graphical view] [Entries sharing at least one domain]

BLOCKS

Search...

Other Resources

DrugBank

DB01065. Melatonin.

SOURCE

Search...

ProtoNet

Search...

Entry information

Entry name

SYUA_HUMAN

Accession

Primary (citable) accession number: P37840
Secondary accession number(s): Q13701, Q4JHI3, Q6IAU6

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1994
Last sequence update:	October 1, 1994
Last modified:	July 22, 2008
This is version 101 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)