A homologue of the Parkinson's disease-associated protein LRRK2 undergoes a monomer-dimer transition during GTP turnover.

TitleA homologue of the Parkinson's disease-associated protein LRRK2 undergoes a monomer-dimer transition during GTP turnover.
Publication TypeJournal Article
Year of Publication2017
AuthorsDeyaert, E., Wauters L., Guaitoli G., Konijnenberg A., Leemans M., Terheyden S., Petrovic A., Gallardo R., Nederveen-Schippers L. M., Athanasopoulos P. S., Pots H., Van Haastert P. J. M., Sobott F., Gloeckner C. Johannes, Efremov R., Kortholt A., and Versées W.
JournalNat Commun
Volume8
Issue1
Pagination1008
Date Published2017 10 18
ISSN2041-1723
KeywordsBacterial Proteins, Chlorobium, Dimerization, Guanosine Triphosphate, Humans, Hydrolysis, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Mutation, Parkinson Disease, Phosphorylation, Protein Structure, Tertiary
Abstract

Mutations in LRRK2 are a common cause of genetic Parkinson's disease (PD). LRRK2 is a multi-domain Roco protein, harbouring kinase and GTPase activity. In analogy with a bacterial homologue, LRRK2 was proposed to act as a GTPase activated by dimerization (GAD), while recent reports suggest LRRK2 to exist under a monomeric and dimeric form in vivo. It is however unknown how LRRK2 oligomerization is regulated. Here, we show that oligomerization of a homologous bacterial Roco protein depends on the nucleotide load. The protein is mainly dimeric in the nucleotide-free and GDP-bound states, while it forms monomers upon GTP binding, leading to a monomer-dimer cycle during GTP hydrolysis. An analogue of a PD-associated mutation stabilizes the dimer and decreases the GTPase activity. This work thus provides insights into the conformational cycle of Roco proteins and suggests a link between oligomerization and disease-associated mutations in LRRK2.

DOI10.1038/s41467-017-01103-4
Alternate JournalNat Commun
PubMed ID29044096
PubMed Central IDPMC5714945
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