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TitleA homologue of the Parkinson's disease-associated protein LRRK2 undergoes a monomer-dimer transition during GTP turnover.
Journal, issue, pagesNat Commun, Vol. 8, Issue 1, Page 1008, Year 2017
Publish dateOct 18, 2017
AuthorsEgon Deyaert / Lina Wauters / Giambattista Guaitoli / Albert Konijnenberg / Margaux Leemans / Susanne Terheyden / Arsen Petrovic / Rodrigo Gallardo / Laura M Nederveen-Schippers / Panagiotis S Athanasopoulos / Henderikus Pots / Peter J M Van Haastert / Frank Sobott / Christian Johannes Gloeckner / Rouslan Efremov / Arjan Kortholt / Wim Versées /
PubMed AbstractMutations 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 ...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.
External linksNat Commun / PubMed:29044096 / PubMed Central
MethodsSAS (X-ray synchrotron)
Structure data

SASDC82:
Rab family protein CtRoco nucleotide free (Rab family protein, CtRoco)
Method: SAXS/SANS

SASDC92: Rab family protein CtRoco GppNHp (Rab family protein, CtRoco)
Method: SAXS/SANS

SASDCA2: Rab family protein CtRoco GDP (Rab family protein, CtRoco)
Method: SAXS/SANS

SASDCB2:
Rab family protein CtRoc-COR nucleotide free (Rab family protein)
Method: SAXS/SANS

SASDCC2: Rab family protein CtRoc-COR GDP (Rab family protein)
Method: SAXS/SANS

SASDCD2: Rab family protein CtRoc-COR GppNHp (Rab family protein)
Method: SAXS/SANS

SASDCE2: Rab family protein CtRoco L487A GDP (Rab family protein, CtRoco)
Method: SAXS/SANS

SASDCF2: Rab family protein CtRoco L487A GppNHp (Rab family protein, CtRoco)
Method: SAXS/SANS

SASDCG2: Rab family protein CtRoco L487A (Rab family protein, CtRoco)
Method: SAXS/SANS

Source
  • Chlorobium tepidum (strain atcc 49652 / dsm 12025 / nbrc 103806 / tls) (bacteria)

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