title: The Parkinson's disease kinase LRRK2 autophosphorylates its GTPase domain at multiple sites.
abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of inherited Parkinson's disease (PD). The protein is large and complex, but pathogenic mutations cluster in a region containing GTPase and kinase domains. LRRK2 can autophosphorylate in vitro within a dimer pair, although the significance of this reaction is unclear. Here, we mapped the sites of autophosphorylation within LRRK2 and found several potential phosphorylation sites within the GTPase domain. Using mass spectrometry, we found that Thr1343 is phosphorylated and, using kinase dead versions of LRRK2, show that this is an autophosphorylation site. However, we also find evidence for additional sites in the GTPase domain and in other regions of the protein suggesting that there may be multiple autophosphorylation sites within LRRK2. These data suggest that the kinase and GTPase activities of LRRK2 may exhibit complex autoregulatory interdependence.
authors.affiliation: Cell Biology and Gene Expression Unit, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892-3707, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: Greggio
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Taymans
authors.forename: Eugene Yuejun
authors.initials: EY
authors.lastname: Zhen
authors.forename: John
authors.initials: J
authors.lastname: Ryder
authors.forename: Renée
authors.initials: R
authors.lastname: Vancraenenbroeck
authors.forename: Alexandra
authors.initials: A
authors.lastname: Beilina
authors.forename: Peng
authors.initials: P
authors.lastname: Sun
authors.forename: Junpeng
authors.initials: J
authors.lastname: Deng
authors.forename: Howard
authors.initials: H
authors.lastname: Jaffe
authors.forename: Veerle
authors.initials: V
authors.lastname: Baekelandt
authors.forename: Kalpana
authors.initials: K
authors.lastname: Merchant
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cookson
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008969:Molecular Sequence Data; D009154:Mutation; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D013912:Threonine / Q000235:genetics / Q000378:metabolism
chemical_list: D013912:Threonine; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D020558:GTP Phosphohydrolases