GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease.

Leucine-rich repeat kinase 2 (LRRK2), a product of a causative gene for the autosomal-dominant form of familial Parkinson's disease (PARK8), harbors a Ras-like small GTP binding protein-like (ROC) domain besides the kinase domain, although the relationship between these two functional domains remains elusive. Here we show by thin-layer chromatographic analysis ...
that LRRK2 stably binds GTP but lacks a GTPase activity in HEK293 and Neuro-2a cells. A ROC domain mutation that converts LRRK2 to a guanine nucleotide-free form (T1348N) abolishes the kinase activity of LRRK2 as well as its phosphate incorporation upon metabolic labeling. The phosphorylation of LRRK2 was inhibited by potential inhibitors for cyclic AMP-dependent protein kinase. These data suggest that binding of GTP to the ROC domain regulates the kinase activity of LRRK2 as well as its phosphorylation by other kinase(s).
Mesh Terms:
Binding Sites, Chromatography, Family Health, GTP Phosphohydrolases, Guanosine Triphosphate, Humans, Mutation, Missense, Parkinson Disease, Phosphorylation, Protein Binding, Protein Kinases, Protein-Serine-Threonine Kinases
Biochemistry
Date: Feb. 06, 2007
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