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Leucine-rich repeat kinase 2 (LRRK2) is a large, complex, multidomain pro-tein 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. S | MINIREVIEW LRRK2 in Parkinson s disease biochemical functions Vasanti S. Anand and Steven P. Braithwaite Wyeth Research Princeton NJ USA Keywords GTpase KESTREL LRRK2 LRRKtide moesin MAPKKK Parkinson s disease serine-threonine kinases specific activity tyrosine-like kinases Correspondence V. S. Anand Wyeth Research Princeton NJ 08543 USA Fax 1 732 274 4020 Tel 1 732 274 4258 E-mail anandv@wyeth.com Received 30 May 2009 revised 9 July 2009 accepted 31 July 2009 doi 10.1111 j.1742-4658.2009.07341.x Leucine-rich repeat kinase 2 LRRK2 is a large complex multidomain protein containing kinase and GTPase enzymatic activities and multiple proteinprotein 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. LRRK2 a multidomain protein with dual enzymatic functions The LRRK2 gene encodes a 2527 amino acid protein with a
