Characterization of Roco proteins

Roco proteins constitute a novel family of Ras-like GTP-proteins, characterized by the presence of a Ras-like Guanine nucleotide binding domain, called Roc (Ras of complex proteins), followed by a COR domain (C-terminal of Roc). Human leucine-rich-repeat kinase 2 (LRRK2) belongs to the Roco family of proteins and has been found to be thus far the most frequent cause of late-onset and idiopathic Parkinson's disease (PD). Importantly, several known pathogenic mutations in LRRK2 result in decreased GTPase activity and enhanced kinase activity, suggesting a possible PD related gain of abnormal/toxic function. Since all attempts to purify mammalian LRRK2 have failed so far, detailed biochemical and structural understanding of LRRK2 is very limited. To elucidate the intramolecular regulatory mechanisms in Roco-proteins, we focus on Dictyostelium discoideum Roco proteins which have are higly similar, but are biochemically more traceable than LRRK2. The genome of the cellular slime mold Dictyostelium discoideum encodes in total for 11 Roco proteins. In particular Roco4 shows the same domain structure and biochemical characteristics as LRRK2. The results presented here show that Dictyostelium roco proteins serves as an excellent model to study the intramolecular regulation of LRRK2 and gives insight in the function and mechanism of LRRK2 activation and how the PD-linked missense mutations alter the interactions between the different domains.