Familial-associated mutations differentially disrupt the solubility, localization, binding and ubiquitination properties of parkin.
Mutations in parkin are largely associated with autosomal recessive juvenile parkinsonism. The underlying mechanism of pathogenesis in parkin-associated Parkinson's disease (PD) is thought to be due to the loss of parkin's E3 ubiquitin ligase activity. A subset of missense and nonsense point mutations in parkin that span the entire gene and represent the numerous inheritance patterns that are associated with parkin-linked PD were investigated for their E3 ligase activity, localization and their ability to bind, ubiquitinate and effect the degradation of two substrates, synphilin-1 and aminoacyl-tRNA synthetase complex cofactor, p38. Parkin mutants vary in their intracellular localization, binding to substrates and enzymatic activity, yet they are ultimately deficient in their ability to degrade substrate. These results suggest that not all parkin mutations result in loss of parkin's E3 ligase activity, but they all appear to manifest as loss-of-function mutants due to defects in solubility, aggregation, enzymatic activity or targeting proteins to the proteasome for degradation.
Pubmed ID: 16049031
- Sriram SR
- Li X
- Ko HS
- Chung KK
- Wong E
- Lim KL
- Dawson VL
- Dawson TM
Human molecular genetics
September 1, 2005
- Agency: NINDS NIH HHS, Id: NS 38377
- Agency: NINDS NIH HHS, Id: NS 48206
- Mutation, Missense
- Parkinson Disease
- Point Mutation
- Polymorphism, Single Nucleotide
- Protein Binding
- Ubiquitin-Protein Ligases
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- Adenocarcinoma of lung, somatic is related to genes PRKN, PARK2, PDJ, LPRS2 which are autosomal recessive according to the OMIM database.
- Leprosy, susceptibility to is related to genes PRKN, PARK2, PDJ, LPRS2.
- Parkinson disease, juvenile, type 2 is related to genes PRKN, PARK2, PDJ, LPRS2 which are autosomal recessive according to the OMIM database.