title: LRRK1 protein kinase activity is stimulated upon binding of GTP to its Roc domain.
abstract: Human leucine-rich repeat kinase 1 (LRRK1) is a multi-domain protein of unknown function belonging to the ROCO family of complex proteins. Here, we report the molecular characterization of human LRRK1 and show, for the first time, that LRRK1 is both a functional protein kinase and a GDP/GTP-binding protein. Binding of GTP to LRRK1 is specific, requires the GTPase-like Roc domain, and leads to a stimulation of LRRK1 kinase activity. LRRK1 is the first example of a GTP-regulated protein kinase harboring both the kinase effector domain and the GTP-binding regulatory domain. Hence, we propose a model in which LRRK1 cycles between a GTP-bound active and a GDP-bound inactive state. Moreover, we mutated LRRK1 to mimic mutations previously identified in LRRK2/dardarin, the only human paralogue of LRRK1, that have been linked to autosomal-dominant parkinsonism. We demonstrate that three of four mutations analyzed significantly downregulate LRRK1 kinase activity. Ultimately, the results presented for LRRK1 may contribute to the elucidation of LRRK2's role in the pathogenesis of Parkinson's disease.
authors.affiliation: Research Laboratories, Schering AG, Muellerstr.178, 13342 Berlin, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Korr
authors.forename: Luisella
authors.initials: L
authors.lastname: Toschi
authors.forename: Peter
authors.initials: P
authors.lastname: Donner
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Pohlenz
authors.forename: Bertolt
authors.initials: B
authors.lastname: Kreft
authors.forename: Bertram
authors.initials: B
authors.lastname: Weiss
mesh_terms: D000595:Amino Acid Sequence; D004789:Enzyme Activation / Q000235:genetics / Q000502:physiology; D006160:Guanosine Triphosphate / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism*; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D046912:Multiprotein Complexes; D006160:Guanosine Triphosphate; C510751:LRRK1 protein, human; D017346:Protein Serine-Threonine Kinases