Home > Publications Database > A homologue of the Parkinson's disease-associated protein LRRK2 undergoes a monomer-dimer transition during GTP turnover. |
Journal Article | DZNE-2020-05889 |
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2017
Nature Publishing Group UK
[London]
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Please use a persistent id in citations: doi:10.1038/s41467-017-01103-4
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.
Keyword(s): Bacterial Proteins: chemistry (MeSH) ; Bacterial Proteins: genetics (MeSH) ; Bacterial Proteins: metabolism (MeSH) ; Chlorobium: chemistry (MeSH) ; Chlorobium: enzymology (MeSH) ; Chlorobium: genetics (MeSH) ; Dimerization (MeSH) ; Guanosine Triphosphate: metabolism (MeSH) ; Humans (MeSH) ; Hydrolysis (MeSH) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: chemistry (MeSH) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics (MeSH) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: metabolism (MeSH) ; Mutation (MeSH) ; Parkinson Disease: enzymology (MeSH) ; Parkinson Disease: genetics (MeSH) ; Phosphorylation (MeSH) ; Protein Structure, Tertiary (MeSH) ; Bacterial Proteins ; Guanosine Triphosphate ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
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