TY  - JOUR
AU  - Deyaert, Egon
AU  - Wauters, Lina
AU  - Guaitoli, Giambattista
AU  - Konijnenberg, Albert
AU  - Leemans, Margaux
AU  - Terheyden, Susanne
AU  - Petrovic, Arsen
AU  - Gallardo, Rodrigo
AU  - Nederveen-Schippers, Laura M
AU  - Athanasopoulos, Panagiotis S
AU  - Pots, Henderikus
AU  - Van Haastert, Peter J M
AU  - Sobott, Frank
AU  - Gloeckner, Christian Johannes
AU  - Efremov, Rouslan
AU  - Kortholt, Arjan
AU  - Versées, Wim
TI  - A homologue of the Parkinson's disease-associated protein LRRK2 undergoes a monomer-dimer transition during GTP turnover.
JO  - Nature Communications
VL  - 8
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2020-05889
SP  - 1008
PY  - 2017
AB  - 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.
KW  - Bacterial Proteins: chemistry
KW  - Bacterial Proteins: genetics
KW  - Bacterial Proteins: metabolism
KW  - Chlorobium: chemistry
KW  - Chlorobium: enzymology
KW  - Chlorobium: genetics
KW  - Dimerization
KW  - Guanosine Triphosphate: metabolism
KW  - Humans
KW  - Hydrolysis
KW  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: chemistry
KW  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics
KW  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: metabolism
KW  - Mutation
KW  - Parkinson Disease: enzymology
KW  - Parkinson Disease: genetics
KW  - Phosphorylation
KW  - Protein Structure, Tertiary
KW  - Bacterial Proteins (NLM Chemicals)
KW  - Guanosine Triphosphate (NLM Chemicals)
KW  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:29044096
C2  - pmc:PMC5714945
DO  - DOI:10.1038/s41467-017-01103-4
UR  - https://pub.dzne.de/record/139567
ER  -