FERM domain interaction with myosin negatively regulates FAK in cardiomyocyte hypertrophy

Area of Science:

• Biochemistry
• Molecular Biology
• Cardiology

Background:

• Focal adhesion kinase (FAK) is crucial for cellular functions in development and disease.
• The N-terminal FERM domain of FAK mediates protein interactions and intramolecular regulation.
• Understanding FAK's regulatory mechanisms is key to addressing related pathologies.

Purpose of the Study:

• To investigate the interaction between the FAK FERM domain and sarcomeric myosin.
• To elucidate the functional consequences of this interaction on FAK activity and cardiac function.
• To explore potential therapeutic strategies targeting this interaction for cardiac hypertrophy.

Main Methods:

• Utilized chemical cross-linking coupled with mass spectrometry (MS).
• Employed small-angle X-ray scattering (SAXS) and computational docking.
• Conducted mutational analyses and used decoy peptides in cardiomyocyte models.

Main Results:

• Identified a molecular cleft in the FAK FERM domain that binds sarcomeric myosin, inhibiting FAK.
• Mutations in the FP-1 sequence within the cleft reduced myosin binding and increased FAK activity in cardiomyocytes.
• An FP-1 decoy peptide mimicked these effects, promoting cardiomyocyte hypertrophy via AKT-mTOR pathway activation.

Conclusions:

• Discovered a novel inhibitory interaction between the FAK FERM domain and sarcomeric myosin.
• This interaction provides a potential target for modulating FAK activity.
• Findings suggest new avenues for therapeutic intervention in cardiac hypertrophy.