Human Molecular Genetics Advance Access originally published online on June 20, 2007
Human Molecular Genetics 2007 16(17):2031-2039; doi:10.1093/hmg/ddm151
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Mechanistic insight into the dominant mode of the Parkinson's disease-associated G2019S LRRK2 mutation
1 Institute of Parasitology and Biomedicine ‘López-Neyra’, Spanish National Research Council (CSIC), 18100 Granada, Spain and 2 Institute of Biomedicine, Spanish National Research Council (CSIC), 46010 Valencia, Spain
* To whom correspondence should be addressed at: Parque Tecnológico de Ciencias de la Salud, Avda del Conocimiento s/n, 18100 Granada, Spain. Tel: +34 958181654; Fax: +34 958181632; Email: sabine.hilfiker{at}ipb.csic.es
Received April 30, 2007; Accepted June 14, 2007
Pathogenic mutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause autosomal-dominant and certain cases of sporadic Parkinson's disease (PD). The G2019S substitution in LRRK2 is the most common genetic determinant of PD identified so far, and maps to a specific region of the kinase domain called the activation segment. Here, we show that autophosphorylation of LRRK2 is an intermolecular reaction and targets two residues within the activation segment. The prominent pathogenic G2019S mutation in LRRK2 results in altered autophosphorylation, and increased autophosphorylation and substrate phosphorylation, through a process that seems to involve reorganization of the activation segment. Our results suggest a molecular mechanistic explanation for how the G2019S mutation enhances the catalytic activity of LRRK2, thereby leading to pathogenicity. These findings have important implications for therapeutic strategies in PD.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  E. Rubio de la Torre, B. Luzon-Toro, I. Forte-Lago, A. Minguez-Castellanos, I. Ferrer, and S. Hilfiker Combined kinase inhibition modulates parkin inactivation Hum. Mol. Genet., March 1, 2009; 18(5): 809 - 823. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Greggio, I. Zambrano, A. Kaganovich, A. Beilina, J.-M. Taymans, V. Daniels, P. Lewis, S. Jain, J. Ding, A. Syed, et al. The Parkinson Disease-associated Leucine-rich Repeat Kinase 2 (LRRK2) Is a Dimer That Undergoes Intramolecular Autophosphorylation J. Biol. Chem., June 13, 2008; 283(24): 16906 - 16914. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Haugarvoll, R. Rademakers, J. M. Kachergus, K. Nuytemans, O. A. Ross, J. M. Gibson, E-K Tan, C. Gaig, E. Tolosa, S. Goldwurm, et al. Lrrk2 R1441C parkinsonism is clinically similar to sporadic Parkinson disease Neurology, April 15, 2008; 70(16_Part_2): 1456 - 1460. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Wang, C. Xie, E. Greggio, L. Parisiadou, H. Shim, L. Sun, J. Chandran, X. Lin, C. Lai, W.-J. Yang, et al. The Chaperone Activity of Heat Shock Protein 90 Is Critical for Maintaining the Stability of Leucine-Rich Repeat Kinase 2 J. Neurosci., March 26, 2008; 28(13): 3384 - 3391. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Liu, X. Wang, Y. Yu, X. Li, T. Wang, H. Jiang, Q. Ren, Y. Jiao, A. Sawa, T. Moran, et al. A Drosophila model for LRRK2-linked parkinsonism PNAS, February 19, 2008; 105(7): 2693 - 2698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Deng, P. A. Lewis, E. Greggio, E. Sluch, A. Beilina, and M. R. Cookson Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase PNAS, February 5, 2008; 105(5): 1499 - 1504. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Cookson, W. Dauer, T. Dawson, E. A. Fon, M. Guo, and J. Shen The Roles of Kinases in Familial Parkinson's Disease J. Neurosci., October 31, 2007; 27(44): 11865 - 11868. [Abstract] [Full Text] [PDF]
|
|