Exploring the interaction between a LRRK2/PP1CA interfering peptide and PP1CA

Parkinson's disease (PD) is a complex neurodegenerative disorder for which there is presently only palliative treatments. Recently, the interaction between the Leucine Reach Repeat Kinase 2 (LRRK2) and the Protein Phosphatase 1 (PP1) has come to light as a priority target for PD, but the way LRRK2 and PP1 interact is currently unknown, hampering the design of modulators. We have previously identified a fragment of LRRK2 able to interfere with the interaction of LRRK2 and PP1 catalytic subunit alpha (PP1CA), and we assume it should bind PP1CA at the LRRK2/PP1CA interface. In this study, we first identify the fragments of PP1CA that are able to interfere with the LRRK2/PP1CA interaction so as to get information about the regions of PP1CA likely to face LRRK2. Next, by combining in silico studies with in vitro competition experiments, we narrow down among the various hypotheses proposed regarding its mode of binding to PP1CA. Overall, we identify one preferred binding mode between the LRRK2 fragment and PP1CA consistent with in vitro results obtained for mutants of the initial fragment. These results pave the way for further rational design of modulators of the LRRK2/PP1CA interaction, to further decipher the molecular mechanisms underlying PD etiology.