%0 Journal Article
%A Deyaert, Egon
%A Wauters, Lina
%A Guaitoli, Giambattista
%A Konijnenberg, Albert
%A Leemans, Margaux
%A Terheyden, Susanne
%A Petrovic, Arsen
%A Gallardo, Rodrigo
%A Nederveen-Schippers, Laura M
%A Athanasopoulos, Panagiotis S
%A Pots, Henderikus
%A Van Haastert, Peter J M
%A Sobott, Frank
%A Gloeckner, Christian Johannes
%A Efremov, Rouslan
%A Kortholt, Arjan
%A Versées, Wim
%T A homologue of the Parkinson's disease-associated protein LRRK2 undergoes a monomer-dimer transition during GTP turnover.
%J Nature Communications
%V 8
%N 1
%@ 2041-1723
%C [London]
%I Nature Publishing Group UK
%M DZNE-2020-05889
%P 1008
%D 2017
%X 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.
%K Bacterial Proteins: chemistry
%K Bacterial Proteins: genetics
%K Bacterial Proteins: metabolism
%K Chlorobium: chemistry
%K Chlorobium: enzymology
%K Chlorobium: genetics
%K Dimerization
%K Guanosine Triphosphate: metabolism
%K Humans
%K Hydrolysis
%K Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: chemistry
%K Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics
%K Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: metabolism
%K Mutation
%K Parkinson Disease: enzymology
%K Parkinson Disease: genetics
%K Phosphorylation
%K Protein Structure, Tertiary
%K Bacterial Proteins (NLM Chemicals)
%K Guanosine Triphosphate (NLM Chemicals)
%K Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:29044096
%2 pmc:PMC5714945
%R 10.1038/s41467-017-01103-4
%U https://pub.dzne.de/record/139567