LRRK2 in Parkinson's disease: biochemical functions.
Leucine-rich repeat kinase 2 (LRRK2) is a large, complex, multidomain protein containing kinase and GTPase enzymatic activities and multiple protein-protein interaction domains. Mutations linked to autosomal dominant forms of Parkinson's disease result in amino acid changes throughout the protein and alterations in both its enzymatic properties and interactions. The best characterized mutation to date, G2019S, leads to increased kinase activity, and mutations in the GTPase domain, such as R1441C and R1441G, have also been reported to influence kinase activity. Therefore, an examination of LRRK2's properties as a kinase is important for understanding the mechanisms underlying the disorder and has the potential to lead to therapeutics. These findings also suggest that there may be complex interplay between the functional domains of LRRK2. Here, we review LRRK2's biochemical functions based on structural and kinetic studies of the enzymatic domains, its potential substrates and the role of its interactions. Despite the field's embryonic understanding of the true relevance of these substrates and interactions, initial studies are providing clues with respect to its pathophysiological functions. Together, these findings should increase our understanding of mechanisms underlying Parkinson's disease and place LRRK2 as a unique molecular target for effective therapeutic development.
Anand
Vasanti S
VS
Wyeth Research, Princeton, NJ 08543, USA. anandv@wyeth.com
Braithwaite
Steven P
SP
D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008954:Models, Biological; D009154:Mutation; D010300:Parkinson Disease / Q000209:etiology* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology
C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases