Journal Article DZNE-2020-05889

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A homologue of the Parkinson's disease-associated protein LRRK2 undergoes a monomer-dimer transition during GTP turnover.

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2017
Nature Publishing Group UK [London]

Nature Communications 8(1), 1008 () [10.1038/s41467-017-01103-4]

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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

Classification:

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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Medline ; Creative Commons Attribution CC BY (No Version) ; DOAJ ; OpenAccess ; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; DOAJ Seal ; IF >= 15 ; JCR ; SCOPUS ; Web of Science Core Collection ; Zoological Record
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 Record created 2020-02-18, last modified 2024-05-11


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