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

被引：115

作者：

Greggio, Elisa ^{[1
]}

Taymans, Jean-Marc ^{[2
]}

Zhen, Eugene Yuejun ^{[3
]}

Ryder, John ^{[3
]}

Vancraenenbroeck, Renee ^{[4
]}

Beilina, Alexandra ^{[1
]}

Sun, Peng ^{[5
]}

Deng, Junpeng ^{[5
]}

Jaffe, Howard ^{[6
]}

Baekelandt, Veerle ^{[2
]}

Merchant, Kalpana ^{[3
]}

Cookson, Mark R. ^{[1
]}

机构：

[1] NIA, Cell Biol & Gene Express Unit, Neurogenet Lab, Bethesda, MD 20892 USA

[2] Katholieke Univ Leuven, Lab Neurobiol & Gene Therapy, Div Mol Med, Dept Mol & Cellular Med, Louvain, Belgium

[3] Eli Lilly & Co, Integrat Biol, Indianapolis, IN 46285 USA

[4] Katholieke Univ Leuven, Dept Chem, Lab Biomol Modelling, Louvain, Belgium

[5] Oklahoma State Univ, Dept Biochem & Mol Biol, Stillwater, OK 74078 USA

[6] NINDS, Prot Peptide Sequencing Facil, NIH, Bethesda, MD 20892 USA

来源：

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS | 2009年 / 389卷 / 03期

关键词：

Parkinson's disease; Kinase; GTPase; Autophosphorylation; LEUCINE-RICH-REPEAT-KINASE-2; LRRK2; PROTEIN; BINDING; MUTATION;

D O I：

10.1016/j.bbrc.2009.08.163

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. Published by Elsevier Inc.

引用

页码：449 / 454

页数：6

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