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Proc Natl Acad Sci U S A. 2014 Mar 18;111(11):4055-60. doi: 10.1073/pnas.1323285111. Epub 2014 Mar 3.

Parkinson disease-associated mutation R1441H in LRRK2 prolongs the "active state" of its GTPase domain.

Author information

1
Department of Biochemistry and Molecular Biology and Stark Neurosciences Institute, Indiana University School of Medicine, Indianapolis, IN 46202.

Abstract

Mutation in leucine-rich-repeat kinase 2 (LRRK2) is a common cause of Parkinson disease (PD). A disease-causing point mutation R1441H/G/C in the GTPase domain of LRRK2 leads to overactivation of its kinase domain. However, the mechanism by which this mutation alters the normal function of its GTPase domain [Ras of complex proteins (Roc)] remains unclear. Here, we report the effects of R1441H mutation (RocR1441H) on the structure and activity of Roc. We show that Roc forms a stable monomeric conformation in solution that is catalytically active, thus demonstrating that LRRK2 is a bona fide self-contained GTPase. We further show that the R1441H mutation causes a twofold reduction in GTPase activity without affecting the structure, thermal stability, and GDP-binding affinity of Roc. However, the mutation causes a twofold increase in GTP-binding affinity of Roc, thus suggesting that the PD-causing mutation R1441H traps Roc in a more persistently activated state by increasing its affinity for GTP and, at the same time, compromising its GTP hydrolysis.

KEYWORDS:

dimer; monomer; neurodegenerative disease; oligomeric states

PMID:
24591621
PMCID:
PMC3964117
DOI:
10.1073/pnas.1323285111
[Indexed for MEDLINE]
Free PMC Article

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