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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 ( LRRK 2)
Author(s) -
Mills Ryan D.,
Mulhern Terrence D.,
Liu Fei,
Culvenor Janetta G.,
Cheng HeungChin
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22515
Subject(s) - lrrk2 , biology , leucine rich repeat , protein kinase domain , protein domain , computational biology , kinase , genetics , microbiology and biotechnology , mutation , gene , mutant
Genetic variations of leucine‐rich repeat kinase 2 ( LRRK 2 ) are the major cause of dominantly inherited P arkinson disease ( PD ). LRRK 2 protein contains seven predicted domains: a tandem Ras‐like GTP ase ( ROC ) domain and C ‐terminal of R oc ( 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 LRRK 2. Determination of the three‐dimensional structure of LRRK 2 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 LRRK 2 have yet to be determined. Based on the known three‐dimensional structures of repeat domains of other proteins, the tandem R oc– COR domains of the C hlorobium tepidum R ab family protein, and the kinase domain of the D ictyostelium discoideum R oco4 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 R oc– COR and kinase domains, and (3) the effects of some PD ‐associated missense variations on the neurotoxic action of LRRK 2. Results of our analysis provide a conceptual framework for future investigation into the regulation and the neurotoxic mechanism of LRRK 2.