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Identification of peptides interfering with the PP2Ac And LRRK2 interaction
Angelita Rebollo1, Samuel Murail2, Pierre Tuffery2
1Unité de Technologies Chimiques et Biologiques pour la Santé, INSERM U1267 - CNRS UMR8258, Université Paris Cité, Faculté de Pharmacie, France.
Biochimica Et Biophysica Acta. Proteins and Proteomics
|April 16, 2026
Summary
Researchers identified key binding sites between protein phosphatase 2 catalytic subunit alpha (PP2Ac) and leucine-rich repeat kinase 2 (LRRK2), a protein linked to Parkinson's disease. These findings offer new tools for studying the PP2Ac/LRRK2 interaction in health and disease.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Parkinson's disease is a neurodegenerative disorder associated with LRRK2 mutations.
- PP2Ac is a key phosphatase implicated in various cellular processes.
- The interaction between LRRK2 and PP2Ac is not fully understood.
Purpose of the Study:
- To identify the specific binding sites between PP2Ac and LRRK2.
- To characterize peptides that mediate the LRRK2/PP2Ac interaction.
- To develop tools for investigating the physiological and pathological roles of this interaction.
Main Methods:
- PEP-scan approach to identify peptide fragments.
- In silico prediction of peptide accessibility.
- In vitro competition assays to assess binding disruption.
- Conformational analysis of peptides.
Main Results:
- Identified binding sites for PP2Ac on LRRK2 and vice versa (mirror peptide).
- Most identified peptide fragments are solvent-accessible and potentially involved in the interaction, except for M2.
- Peptides P3 and M1 effectively competed for PP2A/LRRK2 interaction.
- Peptides P3 and M1 showed a propensity to adopt helical conformations.
Conclusions:
- The study successfully mapped interaction interfaces between PP2Ac and LRRK2.
- Novel peptides (P3, M1) were identified as inhibitors of the PP2Ac/LRRK2 interaction.
- These peptides serve as valuable tools for future research into the role of PP2Ac/LRRK2 signaling in Parkinson's disease and other conditions.
