ROCO kinase activity is controlled by internal GTPase function.
Small guanosine triphosphatases (GTPases) have long been known to control the activities of downstream protein kinases. Some members of a rather new multidomain protein family contain not only a GTPase domain of the ROC (Ras of complex protein) subtype but also a protein kinase domain, and both domains seem to cooperate with each other in the same polypeptide. Data now show that the kinase activity of one of these ROCO proteins depends on whether guanosine diphosphate or guanosine triphosphate (GTP) is bound and that the activity is controlled by the adjacent GTPase, which suggests a novel mechanism of intrinsic control. This ROCO family member, leucine-rich repeat kinase 2 (LRRK2), is of special interest because mutations within both its protein kinase and its GTPase domains are associated with Parkinson's disease (PD). These mutations lead to abnormally enhanced protein kinase activity, which is believed to cause or at least contribute to neuronal damage. The crystal structure of the GTPase domain of LRRK2 has now been resolved and shows that the ROC GTPase domain is responsible for LRRK2 homodimerization in a surprising way. The structure not only offers insights into the molecular effects of some of the PD-associated mutations of LRRK2, but may also help to improve our understanding of the intrinsic control mechanism between a GTPase and a protein kinase within the same protein.
Target Research, Bayer Schering Pharma AG13342, Berlin, Germany. bertram.weiss@bayerhealthcare.com
Bertram
B
Weiss
D019943:Amino Acid Substitution; D019281:Dimerization; D006706:Homeostasis; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008958:Models, Molecular; D009154:Mutation; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
D017853:Phosphotransferases (Alcohol Group Acceptor); C086290:guanosine phosphotransferase; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases