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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)

Authors

  • Ryan D. Mills,

    1. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia
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  • Terrence D. Mulhern,

    1. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia
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  • Fei Liu,

    1. Department of Chemistry & Biomolecular Sciences, Macquarie University, NSW, Australia
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  • Janetta G. Culvenor,

    1. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
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  • Heung-Chin Cheng

    Corresponding author
    1. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia
    • Correspondence to: Heung-Chin Cheng, Department of Biochemistry & Molecular Biology, Bio21 Institute, University of Melbourne, Parkville, Victoria 3010, Australia. E-mail: heung@unimelb.edu.au

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  • Contract grant sponsors: National Health and Medical Research Council of Australia (566743); Australian Brain Foundation; Australian Postgraduate Award, a Dowd Foundation Neuroscience Research Scholarship, and an AINSE (Australian Institute of Nuclear Science and Engineering) Postgraduate Research Award.

  • Communicated by Mauno Vihinen

ABSTRACT

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 on the known three-dimensional structures of repeat domains of other proteins, the tandem Roc–COR domains of the Chlorobium tepidum Rab family protein, and the kinase domain of the Dictyostelium discoideum Roco4 protein, we predicted (1) the motifs essential for protein–protein interactions in all domains, (2) the motifs critical for catalysis and substrate recognition in the tandem Roc–COR and kinase domains, and (3) 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.

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