title: First model of dimeric LRRK2: the challenge of unrevealing the structure of a multidomain Parkinson's-associated protein.
abstract: Mutations within the leucine-rich repeat kinase 2 (LRRK2) gene represent the most common cause of Mendelian forms of Parkinson's disease, among autosomal dominant cases. Its gene product, LRRK2, is a large multidomain protein that belongs to the Roco protein family exhibiting GTPase and kinase activity, with the latter activity increased by pathogenic mutations. To allow rational drug design against LRRK2 and to understand the cross-regulation of the G- and the kinase domain at a molecular level, it is key to solve the three-dimensional structure of the protein. We review here our recent successful approach to build the first structural model of dimeric LRRK2 by an integrative modeling approach.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.|Institute for Ophthalmic Research, Center for Ophthalmology, Eberhard Karls University, 72076 Tübingen, Germany.
authors.forename: Giambattista
authors.initials: G
authors.lastname: Guaitoli
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.
authors.forename: Bernd K
authors.initials: BK
authors.lastname: Gilsbach
authors.affiliation: Cell Networks, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Francesco
authors.initials: F
authors.lastname: Raimondi
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.|Institute for Ophthalmic Research, Center for Ophthalmology, Eberhard Karls University, 72076 Tübingen, Germany.
authors.forename: Christian Johannes
authors.initials: CJ
authors.lastname: Gloeckner
mesh_terms: D001665:Binding Sites / Q000235:genetics; D020558:GTP Phosphohydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics; D010766:Phosphorylation; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary
chemical_list: C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D020558:GTP Phosphohydrolases
keywords: cross-linking; leucine-rich repeat kinase; modeling; structure