Homo- and heterodimerization of ROCO kinases: LRRK2 kinase inhibition by the LRRK2 ROCO fragment

被引:75
作者
Klein, Christian L.
Rovelli, Giorgio [2 ]
Springer, Wolfdieter
Schall, Christoph [3 ]
Gasser, Thomas
Kahle, Philipp J. [1 ]
机构
[1] Univ Clin Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat, Lab Funct Neurogenet, D-72076 Tubingen, Germany
[2] Novartis Pharma AG, Basel, Switzerland
[3] Univ Tubingen, Interfac Inst Biochem, D-72074 Tubingen, Germany
关键词
death-associated protein kinase 1; dimerization; kinase inhibition; leucine-rich repeat kinase 1; leucine-rich repeat kinase 2; Parkinson's disease; AUTOSOMAL-DOMINANT PARKINSONISM; DISEASE-ASSOCIATED MUTATIONS; PROTEIN-KINASE; LEUCINE-RICH-REPEAT-KINASE-2; LRRK2; NEURONAL TOXICITY; GTP-BINDING; GENE LRRK2; ACTIVATION; DOMAIN; DIMERIZATION;
D O I
10.1111/j.1471-4159.2009.06358.x
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 the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common cause of autosomal-dominant familial and late-onset sporadic Parkinson's disease (PD). LRRK2 is a large multi-domain protein featuring a GTP-binding C-terminal of Ras of complex proteins (ROC) (ROCO) domain combination unique for the ROCO protein family, directly followed by a kinase domain. Dimerization is a well-established phenomenon among protein kinases. Here, we confirm LRRK2 self-interaction, and provide evidence for general homo- and heterodimerization potential among the ROCO kinase family (LRRK2, LRRK1, and death-associated protein kinase 1). The ROCO domain was critically, though not exclusively involved in dimerization, as a LRRK2 deletion mutant lacking the ROCO domain retained dimeric properties. GTP binding did not appear to influence ROCOLRRK2 self-interaction. Interestingly, ROCOLRRK2 fragments exerted an inhibitory effect on both wild-type and the elevated G2019S LRRK2 autophosphorylation activity. Insertion of PD mutations into ROCOLRRK2 reduced self-interaction and led to a reduction of LRRK2 kinase inhibition. Collectively, these results suggest a functional link between ROCO interactions and kinase activity of wild-type and mutant LRRK2. Importantly, our finding of ROCOLRRK2 fragment-mediated LRRK2 kinase inhibition offers a novel lead for drug design and thus might have important implications for new therapeutic avenues in PD.
引用
收藏
页码:703 / 715
页数:13
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