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

Jingling Liao, Chun Xiang Wu, Christopher Burlak, Sheng Zhang, Heather Sahm, Mu Wang, Zhong Yin Zhang, Kurt W. Vogel, Mark Federici, Steve M. Riddle, R. Jeremy Nichols, Dali Liu, Mark R. Cookson, Todd A. Stone, Quyen Q. Hoang

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94 Scopus citations


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 showthat 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.

Original languageEnglish (US)
Pages (from-to)4055-4060
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number11
StatePublished - Mar 18 2014


  • Dimer
  • Monomer
  • Neurodegenerative disease
  • Oligomeric states


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