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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.

SUBMITTER: Greggio E 

PROVIDER: S-EPMC2759846 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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The Parkinson's disease kinase LRRK2 autophosphorylates its GTPase domain at multiple sites.

Greggio Elisa E   Taymans Jean-Marc JM   Zhen Eugene Yuejun EY   Ryder John J   Vancraenenbroeck Renée R   Beilina Alexandra A   Sun Peng P   Deng Junpeng J   Jaffe Howard H   Baekelandt Veerle V   Merchant Kalpana K   Cookson Mark R MR  

Biochemical and biophysical research communications 20090903 3


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,  ...[more]

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