This study maps PP2Ac–LRRK2 interaction sites using PEP-scan and identifies two peptides (P3, M1) that compete with the PP2A/LRRK2 interaction in vitro.

LRRK2 is a major Parkinson's disease-linked protein, so peptides that disrupt its interaction with PP2A are useful mechanistic tools with potential therapeutic relevance, but the work lacks cellular, functional, or in vivo validation needed for strong translational impact.

Using the PEP-scan approach, we have identified the binding site of PP2Ac to LRRK2, a protein associated with Parkinson's disease. We also have identified the binding site of LRRK2 to PP2Ac, referred to as mirror peptide. All isolated fragments are predicted to be solvent-accessible and are compatible with contributing to LRRK2/PP2Ac interaction except for peptide M2. The In vitro competition experiment demonstrated that peptide P3 and M1 effectively compete PP2A/LRRK2 interaction. Both appear to have propensity to adopt helical conformation. These newly generated peptides can be tools to investigate the role of PP2A/LRRK2 interaction under both physiological and pathological conditions.