Prediction of the repeat domain structures and impact of parkinsonism-associated variations on structure and function of all functional domains of Leucine-rich repeat kinase 2 (LRRK2)
AuthorMills, Ryan D.; Mulhern, Terrence D.; Liu, Fei; Culvenor, Janetta G.; Cheng, Heung-Chin
Source TitleHuman Mutation
University of Melbourne Author/sMILLS, RYAN; Mulhern, Terry; Liu, Fei; Culvenor, Janetta; Cheng, Heung-Chin
AffiliationBiochemistry and Molecular Biology
Department of Biochemistry and Molecular Biology
Bio21 Molecular Science and Biotechnology Institute
Department of Pathology
Document TypeJournal Article
CitationsMills, R. D., Mulhern, T. D., Liu, F., Culvenor, J. G., & Cheng, H. (2014). Prediction of the repeat domain structures and impact of parkinsonism-associated variations on structure and function of all functional domains of Leucine-rich repeat kinase 2 (LRRK2) . Human Mutation, 35(4), 395-412.
Access StatusThis item is currently not available from this repository
NHMRC Grant codeNHMRC/566743
© 2013 Wiley Periodicals Inc.
The research outputs in this collection have been funded in whole or in part by the National Health and Medical Research Council (NHMRC).
Genetic variations of leucine-rich repeat kinase 2 (LRRK2) are the major cause of dominantly inherited Parkinson disease (PD). LRRK2 protein contains seven predicted domains: a tandem Ras-like GTPase (ROC) domain and C-terminal of Roc (COR) domain, a protein kinase domain and four repeat domains. PD-causative variations arise in all domains, suggesting that aberrant functioning of any domain can contribute to neurotoxic mechanisms of LRRK2. Determination of the three-dimensional structure of LRRK2 is one of the best avenues to decipher its neurotoxic mechanism. However, with the exception of the Roc domain, the three-dimensional structures of the functional domains of LRRK2 have yet to be determined. Based upon the known three-dimensional structures of repeat domains of other proteins, the tandem Roc-COR domains of the C. tepidum Rab family protein, and the kinase domain of the D. discoideum Roco4 protein, we predicted (i) the motifs essential for protein-protein interactions in all domains, (ii) the motifs critical for catalysis and substrate recognition in the tandem Roc-COR and kinase domains, and (iii) the effects of some PD-associated missense variations on the neurotoxic action of LRRK2. Results of our analysis provide a conceptual framework for future investigation into the regulation and the neurotoxic mechanism of LRRK2.
KeywordsLRRK2; protein kinase; protein interactions; phosphorylation; neurotoxicity; Parkinson disease
- Click on "Export Reference in RIS Format" and choose "open with... Endnote".
- Click on "Export Reference in RIS Format". Login to Refworks, go to References => Import References