Leucine-rich repeat kinase 2 binds to neuronal vesicles through protein interactions mediated by its C-terminal WD40 domain.
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Piccoli G, Onofri F, Cirnaru MD, Kaiser CJ, Jagtap P, Kastenmuller A, Pischedda F, Marte A, von Zweydorf F, Vogt A, Giesert F, Pan L, Antonucci F, Kiel C, Zhang M, Weinkauf S, Sattler M, Sala C, Matteoli M, Ueffing M, Gloeckner CJ
Leucine-rich repeat kinase 2 binds to neuronal vesicles through protein interactions mediated by its C-terminal WD40 domain.
Mol Cell Biol. 2014 Jun;34(12):2147-61. doi: 10.1128/MCB.00914-13. Epub 2014 Mar 31.
- PubMed ID
- 24687852 [ View in PubMed]
- Abstract
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.