Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 34, Issue 12, Pages 2147-2161Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00914-13
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Funding
- National Genome Research Framework program NGFN-Plus [01GS08140]
- Helmholtz Alliance for Mental Health in an Aging Society [HA-215, WP11]
- European Community's [241955, 278568]
- PRIMES [241481]
- AFFINOMICS
- LRRK2 Biology LEAPS 2012 of the Michael J. Fox Foundation
- Fondazione Cariplo [2011-0540, 2008-3184]
- MJFF, and Fondazione Telethon [GGP12237]
- FIRB program [RBFR08F82X_002]
- Fondazione Grigioni per il morbo di Parkinson
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Mutations in the 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 the 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 vesicles via interaction with vesicle-associated proteins. In fact, a domain- based pulldown 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 the WD40 domain within LRRK2 function.
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