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Title
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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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Author
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Abstract
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| 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. |
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Language
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English
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Source (journal)
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Nature communications
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Publication
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2017
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ISSN
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2041-1723
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DOI
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10.1038/S41467-017-01103-4
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Volume/pages
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8
(2017)
, 12 p.
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Article Reference
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1008
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ISI
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000413168700004
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Pubmed ID
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29044096
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Medium
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E-only publicatie
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Full text (Publisher's DOI)
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Full text (open access)
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