tailieunhanh - Báo cáo khoa học: Investigation of leucine-rich repeat kinase 2 Enzymological properties and novel assays

Mutations in leucine-rich repeat kinase 2 (LRRK2) comprise the leading cause of autosomal dominant Parkinson’s disease, with age of onset and symptoms identical to those of idiopathic forms of the disorder. Several of these pathogenic mutations are thought to affect its kinase activity, so understanding the roles of LRRK2, and modulation of its kinase activity, may lead to novel therapeutic strategies for treating Parkinson’s disease. | ễFEBS Journal Investigation of leucine-rich repeat kinase 2 Enzymological properties and novel assays Vasanti S. Anand1 Laurie J. Reichling2 Kerri Lipinski1 Wayne Stochaj3 Weili Duan3 Kerry Ịốol lohot 3 Paai a Pl InnaIi a4 p I inono I RrcuA n4 Potnr I I Roi n har 1 Rinharrl omKom2 A arron eeei ooja ungaya ugene . I own eter . einait cai omeig alien D. Hirst1 Steven M. Riddle2 and Steven P. Braithwaite1 1 Wyeth Research Discovery Neuroscience Princeton NJ USA 2 Invitrogen Corporation Discovery Sciences Madison WI USA 3 Wyeth Research Chemicaland Screening Sciences Cambridge MA USA 4 Wyeth Research BiologicalTechnologies Cambridge MA USA Keywords LanthaScreen LRRK2 LRRKtide moesin Parkinson s disease Correspondence S. P. Braithwaite Wyeth Research Discovery Neuroscience Princeton CN8000 NJ 08543 USA Fax 1 732 274 4020 Tel 1 732 274 4556 E-mail braiths@ Received 18 May 2008 revised 11 November 2008 accepted 12 November 2008 doi Mutations in leucine-rich repeat kinase 2 LRRK2 comprise the leading cause of autosomal dominant Parkinson s disease with age of onset and symptoms identical to those of idiopathic forms of the disorder. Several of these pathogenic mutations are thought to affect its kinase activity so understanding the roles of LRRK2 and modulation of its kinase activity may lead to novel therapeutic strategies for treating Parkinson s disease. In this study highly purified baculovirus-expressed proteins have been used for the first time providing large amounts of protein that enable a thorough enzymatic characterization of the kinase activity of LRRK2. Although LRRK2 undergoes weak autophosphorylation it exhibits high activity towards the peptidic substrate LRRKtide suggesting that it is a catalytically efficient kinase. We have also utilized a time-resolved fluorescence resonance energy transfer TR-FRET assay format Lantha-ScreenTM to characterize LRRK2 and test the effects of nonselective kinase inhibitors. Finally

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