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

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 ROCO LRRK2 self‐interaction. Interestingly, ROCO LRRK2 fragments exerted an inhibitory effect on both wild‐type and the elevated G2019S LRRK2 autophosphorylation activity. Insertion of PD mutations into ROCO LRRK2 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 ROCO LRRK2 fragment‐mediated LRRK2 kinase inhibition offers a novel lead for drug design and thus might have important implications for new therapeutic avenues in PD.