ジャーナル: Nat Commun / 年: 2017 タイトル: A homologue of the Parkinson's disease-associated protein LRRK2 undergoes a monomer-dimer transition during GTP turnover. 著者: Egon Deyaert / Lina Wauters / Giambattista Guaitoli / Albert Konijnenberg / Margaux Leemans / Susanne Terheyden / Arsen Petrovic / Rodrigo Gallardo / Laura M Nederveen-Schippers / Panagiotis ...著者: Egon Deyaert / Lina Wauters / Giambattista Guaitoli / Albert Konijnenberg / Margaux Leemans / Susanne Terheyden / Arsen Petrovic / Rodrigo Gallardo / Laura M Nederveen-Schippers / Panagiotis S Athanasopoulos / Henderikus Pots / Peter J M Van Haastert / Frank Sobott / Christian Johannes Gloeckner / Rouslan Efremov / Arjan Kortholt / Wim Versées / 要旨: 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 ...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.
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Egon Deyaert (VUB, Vrije Universiteit Brussel, Pleinlaan 2 1050 Brussel)