Leucine-Rich Repeat Kinase 2 Binds to Neuronal Vesicles through Protein Interactions Mediated by Its C-Terminal WD40 Domain | Zendy

Giovanni Piccoli | Zendy; Franco Onofri | Zendy; Maria Daniela Cirnaru | Zendy; Christoph J. O. Kaiser | Zendy; Pravin Kumar Ankush Jagtap | Zendy; Andreas Kastenmüller | Zendy; Francesca Pischedda | Zendy; Antonella Marte | Zendy; Felix von Zweydorf | Zendy; Andreas Vogt | Zendy; Florian Giesert | Zendy; Lifeng Pan | Zendy; Flavia Antonucci | Zendy; Christina Kiel | Zendy; Mingjie Zhang | Zendy; Sevil Weinkauf | Zendy; Michael Sattler | Zendy; Carlo Sala | Zendy; Michela Matteoli | Zendy; Marius Ueffing | Zendy; Christian Johannes Gloeckner | Zendy

Open Access

Leucine-Rich Repeat Kinase 2 Binds to Neuronal Vesicles through Protein Interactions Mediated by Its C-Terminal WD40 Domain

Author(s) -

Giovanni Piccoli,

Franco Onofri,

Maria Daniela Cirnaru,

Christoph J. O. Kaiser,

Pravin Kumar Ankush Jagtap,

Andreas Kastenmüller,

Francesca Pischedda,

Antonella Marte,

Felix von Zweydorf,

Andreas Vogt,

Florian Giesert,

Lifeng Pan,

Flavia Antonucci,

Christina Kiel,

Mingjie Zhang,

Sevil Weinkauf,

Michael Sattler,

Carlo Sala,

Michela Matteoli,

Marius Ueffing,

Christian Johannes Gloeckner

Publication year - 2014

Publication title -

molecular and cellular biology

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.14

H-Index - 327

eISSN - 1067-8824

pISSN - 0270-7306

DOI - 10.1128/mcb.00914-13

Subject(s) - lrrk2 , leucine rich repeat , biology , synaptic vesicle , vesicle , protein kinase domain , microbiology and biotechnology , protein domain , kinase , plasma protein binding , biochemistry , protein–protein interaction , gene , mutation , membrane , mutant

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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