Journal Article

DZNE-2020-05889

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A homologue of the Parkinson's disease-associated protein LRRK2 undergoes a monomer-dimer transition during GTP turnover.

Deyaert, E. ; Wauters, L. ; Guaitoli, G.DZNE* ; 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.DZNE* ; Efremov, R. ; Kortholt, A. ; Versées, W. (Corresponding author)

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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Contributing Institute(s):

1. Functional Neuroproteomics and Translational Biomarkers in Neurodegenerative Diseases (AG Gloeckner)

Research Program(s):

1. 345 - Population Studies and Genetics (POF3-345) (POF3-345)

Appears in the scientific report 2017

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