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@ARTICLE{Deyaert:139567,
author = {Deyaert, Egon and Wauters, Lina and Guaitoli, Giambattista
and Konijnenberg, Albert and Leemans, Margaux and Terheyden,
Susanne and Petrovic, Arsen and Gallardo, Rodrigo and
Nederveen-Schippers, Laura M and Athanasopoulos, Panagiotis
S and Pots, Henderikus and Van Haastert, Peter J M and
Sobott, Frank and Gloeckner, Christian Johannes and Efremov,
Rouslan and Kortholt, Arjan and Versées, Wim},
title = {{A} homologue of the {P}arkinson's disease-associated
protein {LRRK}2 undergoes a monomer-dimer transition during
{GTP} turnover.},
journal = {Nature Communications},
volume = {8},
number = {1},
issn = {2041-1723},
address = {[London]},
publisher = {Nature Publishing Group UK},
reportid = {DZNE-2020-05889},
pages = {1008},
year = {2017},
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.},
keywords = {Bacterial Proteins: chemistry / Bacterial Proteins:
genetics / Bacterial Proteins: metabolism / Chlorobium:
chemistry / Chlorobium: enzymology / Chlorobium: genetics /
Dimerization / Guanosine Triphosphate: metabolism / Humans /
Hydrolysis / Leucine-Rich Repeat Serine-Threonine Protein
Kinase-2: chemistry / Leucine-Rich Repeat Serine-Threonine
Protein Kinase-2: genetics / Leucine-Rich Repeat
Serine-Threonine Protein Kinase-2: metabolism / Mutation /
Parkinson Disease: enzymology / Parkinson Disease: genetics
/ Phosphorylation / Protein Structure, Tertiary / Bacterial
Proteins (NLM Chemicals) / Guanosine Triphosphate (NLM
Chemicals) / Leucine-Rich Repeat Serine-Threonine Protein
Kinase-2 (NLM Chemicals)},
cin = {AG Gloeckner},
ddc = {500},
cid = {I:(DE-2719)1210007},
pnm = {345 - Population Studies and Genetics (POF3-345)},
pid = {G:(DE-HGF)POF3-345},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:29044096},
pmc = {pmc:PMC5714945},
doi = {10.1038/s41467-017-01103-4},
url = {https://pub.dzne.de/record/139567},
}