title: The unconventional G-protein cycle of LRRK2 and Roco proteins.
abstract: Mutations in the human leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of hereditary Parkinson's disease (PD). LRRK2 belongs to the Roco family of proteins, which are characterized by the presence of a Ras of complex proteins domain (Roc), a C-terminal of Roc domain (COR) and a kinase domain. Despite intensive research, much remains unknown about activity and the effect of PD-associated mutations. Recent biochemical and structural studies suggest that LRRK2 and Roco proteins are noncanonical G-proteins that do not depend on guanine nucleotide exchange factors or GTPase-activating proteins for activation. In this review, we will discuss the unusual G-protein cycle of LRRK2 in the context of the complex intramolecular LRRK2 activation mechanism.
authors.affiliation: Department of Cell Biochemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands.
authors.forename: Susanne
authors.initials: S
authors.lastname: Terheyden
authors.affiliation: Department of Cell Biochemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Nederveen-Schippers
authors.affiliation: Department of Cell Biochemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands.
authors.forename: Arjan
authors.initials: A
authors.lastname: Kortholt
mesh_terms: D019204:GTP-Binding Proteins / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006153:Guanosine Diphosphate / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D019204:GTP-Binding Proteins
keywords: G-proteins activated by nucleotide-dependent dimerization (GAD); Parkinson's disease; Roco proteins; leucine-rich repeat kinase 2 (LRRK2)