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 Hoang

Research output: Contribution to journalArticle

63 Citations (Scopus)

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 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
Pages (from-to)4055-4060
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number11
DOIs
StatePublished - Mar 18 2014

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GTP Phosphohydrolases
Leucine
Parkinson Disease
Phosphotransferases
Mutation
Guanosine Triphosphate
ras Proteins
Point Mutation
Hydrolysis
Hot Temperature

Keywords

  • Dimer
  • Monomer
  • Neurodegenerative disease
  • Oligomeric states

ASJC Scopus subject areas

  • General

Cite this

Parkinson disease-associated mutation R1441H in LRRK2 prolongs the "active state" of its GTPase domain. / Liao, Jingling; Wu, Chun Xiang; Burlak, Christopher; Zhang, Sheng; Sahm, Heather; Wang, Mu; Zhang, Zhong-Yin; Vogel, Kurt W.; Federici, Mark; Riddle, Steve M.; Nichols, R. Jeremy; Liu, Dali; Cookson, Mark R.; Stone, Todd A.; Hoang, Quyen.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 11, 18.03.2014, p. 4055-4060.

Research output: Contribution to journalArticle

Liao, J, Wu, CX, Burlak, C, Zhang, S, Sahm, H, Wang, M, Zhang, Z-Y, Vogel, KW, Federici, M, Riddle, SM, Nichols, RJ, Liu, D, Cookson, MR, Stone, TA & Hoang, Q 2014, 'Parkinson disease-associated mutation R1441H in LRRK2 prolongs the "active state" of its GTPase domain', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 11, pp. 4055-4060. https://doi.org/10.1073/pnas.1323285111
Liao, Jingling ; Wu, Chun Xiang ; Burlak, Christopher ; Zhang, Sheng ; Sahm, Heather ; Wang, Mu ; Zhang, Zhong-Yin ; Vogel, Kurt W. ; Federici, Mark ; Riddle, Steve M. ; Nichols, R. Jeremy ; Liu, Dali ; Cookson, Mark R. ; Stone, Todd A. ; Hoang, Quyen. / Parkinson disease-associated mutation R1441H in LRRK2 prolongs the "active state" of its GTPase domain. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 11. pp. 4055-4060.
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AU - Sahm, Heather

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AU - Nichols, R. Jeremy

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AB - 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.

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