|Title||A homologue of the Parkinson's disease-associated protein LRRK2 undergoes a monomer-dimer transition during GTP turnover.|
|Publication Type||Journal Article|
|Year of Publication||2017|
|Authors||Deyaert, E., L. Wauters, G. Guaitoli, A. Konijnenberg, M. Leemans, S. Terheyden, A. Petrovic, R. Gallardo, L. M. Nederveen-Schippers, P. S. Athanasopoulos, H. Pots, P. J. M. Van Haastert, F. Sobott, C. Johannes Gloeckner, R. G. Efremov, A. Kortholt, and W. Versées|
|Date Published||2017 10 18|
|Keywords||Bacterial Proteins, Chlorobium, Dimerization, Guanosine Triphosphate, Humans, Hydrolysis, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Mutation, Parkinson Disease, Phosphorylation, Protein Structure, Tertiary|
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.
|Alternate Journal||Nat Commun|
|PubMed Central ID||PMC5714945|
A homologue of the Parkinson's disease-associated protein LRRK2 undergoes a monomer-dimer transition during GTP turnover.