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Structural and functional in silico analysis of LRRK2 missense substitutions

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Abstract

The LRRK2 gene (Leucine-Rich Repeat Kinase 2, PARK8) is mutated in a significant number of cases of autosomal dominant Parkinson’s disease (PD) and in some sporadic cases of late-onset PD. LRRK2 is a large, complex protein that comprises several interaction domains: armadillo, ankyrin, leucine-rich repeats and WD40 domains; two catalytic domains: ROC-GTPase and serine/threonine kinase; and a COR domain (unknown function). Pathogenic mutations are scattered all over the domains of LRRK2, although the prevalence of mutations in some domains is higher (ROC-GTPase, COR and kinase). In this work, we model the structure of each domain to predict and explore the effects of described missense mutations and polymorphisms. The results allow us to postulate the possible effects of pathogenic mutations in the function of the protein, and hypothesize the importance of some polymorphisms that have not been linked directly to PD, but act as risk factors for the disease. In our analysis, we also study the effects of PD-related mutations in the kinase domain structure and in the phosphorylation of the activation loop to determine effects on kinase activity.

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Acknowledgments

The authors wish to thank the different departments at the IBV for their help and assistance in developing this project. The authors also wish to state that have no conflict of interest to declare. Contract Grant sponsor: The Ministerio de Ciencia e Innovación, Spain; Contract Grant number: SAF2009-10434; Contract Grant sponsor: Generalitat Valenciana; Contract Grant number: ACOMP/2010/096.

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  1. Marta Tormos-Pérez

    Present address: Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC), Salamanca University, Salamanca, Spain

Authors and Affiliations

  1. Unitat de Genètica Molecular, Institut de Biomedicina de València, Consejo Superior de Investigaciones Científicas (IBV-CSIC), Jaume Roig 11, 46010, Valencia, Spain

    Fernando Cardona, Marta Tormos-Pérez & Jordi Pérez-Tur

  2. CiberNed, Madrid, Spain

    Fernando Cardona & Jordi Pérez-Tur

  3. Departamento de Biotecnología, Escuela Técnica Superior de Ingenieros Agrónomos, Universitat Politécnica de València, Valencia, Spain

    Marta Tormos-Pérez

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  1. Fernando Cardona
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  2. Marta Tormos-Pérez
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Correspondence to Fernando Cardona or Jordi Pérez-Tur.

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Cardona, F., Tormos-Pérez, M. & Pérez-Tur, J. Structural and functional in silico analysis of LRRK2 missense substitutions. Mol Biol Rep 41, 2529–2542 (2014). https://doi.org/10.1007/s11033-014-3111-z

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