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

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 and Wim Versées ()
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Egon Deyaert: VIB-VUB Center for Structural Biology
Lina Wauters: VIB-VUB Center for Structural Biology
Giambattista Guaitoli: German Center for Neurodegenerative Diseases (DZNE)
Albert Konijnenberg: University of Antwerp
Margaux Leemans: VIB-VUB Center for Structural Biology
Susanne Terheyden: University of Groningen
Arsen Petrovic: Max-Planck Institute of Molecular Physiology
Rodrigo Gallardo: VIB Center for Brain & Disease Research
Laura M. Nederveen-Schippers: University of Groningen
Panagiotis S. Athanasopoulos: University of Groningen
Henderikus Pots: University of Groningen
Peter J. M. Van Haastert: University of Groningen
Frank Sobott: University of Antwerp
Christian Johannes Gloeckner: German Center for Neurodegenerative Diseases (DZNE)
Rouslan Efremov: VIB-VUB Center for Structural Biology
Arjan Kortholt: University of Groningen
Wim Versées: VIB-VUB Center for Structural Biology

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01103-4

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