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synphilin-1; sph1; alpha-synuclein-interacting protein (SNCAIP)
Function:
- associates with alpha-synuclein
- ubiquitinated; mediated by SIAH1, SIAH2 or RNF19A & leading to its subsequent proteasomal degradation
- in the absence of proteasomal degradation, ubiquitinated SNCAIP accumulates in cytoplasmic inclusion bodies
- homodimer (probable)
- heterodimer of isoform 1 & isoform 2 (probable)
- interacts with SIAH1, SIAH2, SNCA, RNF19A & PARK2
- isoform 2
a) inhibits the ubiquitin ligase activity of SIAH1 & inhibits proteasomal degradation of target proteins
b) inhibits autoubiquitination & proteasomal degradation of SIAH1, & thereby increases cellular levels of SIAH
c) modulates SNCA monoubiquitination by SIAH1
d) is subject to limited ubiquitination that does not lead to proteasomal degradation
e) has a strong tendency to form aggregates & can sequester isoform 1
Structure:
- contains 6 ANK repeats
Compartment:
- cytoplasm
- detected in cytoplasmic inclusion bodies, together with SNCA
Alternative splicing: named isoforms=6
Expression:
- detected in brain (at protein level)
- widely expressed, with highest levels in brain, heart & placenta
Pathology:
- defects in SNCAIP are a cause of Parkinson disease
- promotes formation of cytoplasmic inclusions
- detected in some Lewy bodies, but not Lewy neurites
Notes:
- constructs encoding portions of SNCA & SNCAIP co-transfected in mammalian cells promote cytosolic inclusions resembling the Lewy bodies of Parkinson disease
- coexpression of SNCA, SNCAIP, & PARK2 result in the formation of Lewy body-like ubiquitin-positive cytosolic inclusions
- SNCAIP isoform 2 is particularly aggregatation-prone
- familial mutations in PARK2 disrupt the ubiquitination of SNCAIP & the formation of the ubiquitin-positive inclusions
- ubiquitination of Lewy body-associated proteins link PARK2 & SNCA in a common pathogenic mechanism through their interaction with SNCAIP
General
ankyrin repeat domain protein (ANKRD)
phosphoprotein
Properties
SIZE: entity length = 919 aa
MW = 100 kD
COMPARTMENT: cytoplasm
MOTIF: ankyrin repeat
NAME: ankyrin repeat
SITE: 349-380
ankyrin repeat
NAME: ankyrin repeat
SITE: 384-413
MOTIF: Thr phosphorylation site {T387}
ankyrin repeat
NAME: ankyrin repeat
SITE: 419-448
ankyrin repeat
NAME: ankyrin repeat
SITE: 456-485
coiled coil {515-552}
ankyrin repeat
NAME: ankyrin repeat
SITE: 603-632
ankyrin repeat
NAME: ankyrin repeat
SITE: 699-729
Database Correlations
OMIM correlations
UniProt Q9Y6H5
Pfam PF00023
Entrez Gene 9627
Kegg hsa:9627
References
- UniProt :accession Q9Y6H5
- GeneReviews
http://www.ncbi.nlm.nih.gov/sites/genetests/lab/gene/SNCAIP
- Engelender S et al
Synphilin-1 associates with alpha-synuclein and promotes the
formation of cytosolic inclusions.
Nature Genetics 22:110-114, 1999
PMID: 10319874
- Goedert M
Alpha-synuclein and neurodegenerative diseases.
Nature Reviews neuroscience 2:492-501, 2001
PMID: 11433374