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Open Access Green as soon as Postprint is submitted to ZB.
Leucine-rich repeat kinase 2 binds to neuronal vesicles through protein interactions mediated by its C-terminal WD40 domain.
Mol. Cell. Biol. 34, 2147-2161 (2014)
Mutations in leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial and sporadic Parkinson's disease (PD). LRRK2 is a complex protein that consists of multiple domains, including predicted C-terminal WD40 repeats. In this study we analyzed functional and molecular features conferred by the WD40 domain. Electron microscopic analysis of purified LRRK2 C-terminal domain revealed doughnut-shaped particles, providing experimental evidence for its WD40 fold. We demonstrate that LRRK2 WD40 binds and sequesters synaptic vesicle via interaction with vesicle-associated proteins. In fact, a domain-based pull-down approach combined with mass spectrometric analysis identified LRRK2 as being part of a highly specific protein network involved in synaptic vesicle trafficking. In addition, we found that a C-terminal sequence variant associated with an increased risk of developing PD, G2385R, correlates with a reduced binding affinity of LRRK2 WD40 to synaptic vesicles. Our data demonstrate a critical role of WD40 domain within LRRK2 function.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Parkinsons-disease; Hippocampal-neurons; Interaction Networks; Synaptic Vesicles; Statistical-model; Lrrk2 Gly2385arg; Synapsin-i; Data-bank; Mutation; Variant
ISSN (print) / ISBN
0270-7306
e-ISSN
1098-5549
Journal
Molecular and Cellular Biology
Quellenangaben
Volume: 34,
Issue: 12,
Pages: 2147-2161
Publisher
American Society for Microbiology (ASM)
Publishing Place
Washington
Non-patent literature
Publications
Reviewing status
Peer reviewed