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Structural insights into the Roco G-protein cycle

The Roco protein family has come into the focus of research when the human Roco protein LRRK2 (Leucine-rich repeat kinase 2) was discovered to be the most frequent cause of late onset Parkinson’s disease (PD). Roco proteins are characterized by the RocCOR domain tandem, consisting of a Ras-of-complex proteins (Roc) G-domain and a C-terminal-of-Roc (COR) dimerization domain. Although our understanding of the function and regulation mechanism of Roco proteins is still preliminary, evidence is accumulating that the Roc domain is not a classical G-domain but follows an unconventional activation mechanism. Structural data on Roco proteins are rare but would be very valuable in order to describe the activation mechanism and regulation of the RocCOR tandem domain. Here we report for the first time a nucleotide bound structure of the full RocCOR tandem from Methanosarcina barkeri (Mb). Comparison of the GppNHp and GDP bound states reveal no major differences in the switch region, in contrast to conformational changes reported for classical small G-proteins such as Ras, thus underscoring an unconventional switch mechanism of Roco proteins. Moreover the structure of a mutation homologous to the PD associated mutation Y1699C in LRRK2 could be solved. Structure and biochemical analysis lead to the assumption of a change in the flexibility of the mutant protein.