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

Deyaert, 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. J., Efremov, R., Kortholt, A. & Versées, W., 18-Oct-2017, In : Nature Communications. 8, 1, p. 1-12 12 p., 1008.

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Article number1008
Pages (from-to)1-12
Number of pages12
JournalNature Communications
Volume8
Issue number1
Publication statusPublished - 18-Oct-2017

    Keywords

  • Parkinson's disease, LRRK2, protein conformation, transition, GTP-binding
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