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
Number of pages12
JournalNature Communications
Issue number1
Publication statusPublished - 18 Oct 2017

    Research areas

  • Bacterial Proteins/chemistry, Chlorobium/chemistry, Dimerization, Guanosine Triphosphate/metabolism, Humans, Hydrolysis, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/chemistry, Mutation, Parkinson Disease/enzymology, Phosphorylation, Protein Structure, Tertiary

ID: 35723637