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

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2014-03, Vol.111 (11), p.4055-4060
Main Authors: Liao, Jingling, Wu, Chun-Xiang, Burlak, Christopher, Zhang, Sheng, Sahm, Heather, Mu Wang, Zhang, Zhong-Yin, Vogel, Kurt W., Federici, Mark, Riddle, Steve M., Nichols, R. Jeremy, Liu, Dali, Cookson, Mark R., Stone, Todd A., Hoang, Quyen Q.
Format: Article
Language:English
Subjects:
Biochemistry
Biological Sciences
Blotting, Western
Chromatography, Gel
Circular Dichroism
Dimerization
Dimers
Electrophoresis, Polyacrylamide Gel
Enzymes
Genetic mutation
GTP Phosphohydrolases - genetics
GTP Phosphohydrolases - metabolism
Humans
Hydrolysis
Kinases
Kinetics
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Mass Spectrometry
Models, Molecular
Monomers
Mutation, Missense - genetics
Nucleotides
Parkinson disease
Parkinson Disease - genetics
Parkinson's disease
Protein Conformation
Protein-Serine-Threonine Kinases - chemistry
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Proteins
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1323285111