FERM domain interaction with myosin negatively regulates FAK in cardiomyocyte hypertrophy

• Published in: Nature chemical biology Vol. 8; no. 1; pp. 102 - 110
• Main Authors: Santos, Aline M, Schechtman, Deborah, Cardoso, Alisson C, Clemente, Carolina F M Z, Silva, Júlio C, Fioramonte, Mariana, Pereira, Michelle B M, Marin, Talita M, Oliveira, Paulo S L, Figueira, Ana Carolina M, Oliveira, Saulo H P, Torriani, Íris L, Gozzo, Fábio C, Neto, José Xavier, Franchini, Kleber G
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2012
• Subjects: 631/443/592/1540; 631/45/535; 631/80/86; 631/92/607/275; Amino Acid Sequence; Animals; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Cell Biology; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Chickens; Enzyme Activation; Focal Adhesion Protein-Tyrosine Kinases - chemistry; Focal Adhesion Protein-Tyrosine Kinases - metabolism; Hypertrophy - metabolism; Mice; Models, Molecular; Myocytes, Cardiac - chemistry; Myocytes, Cardiac - metabolism; Myosins - chemistry; Myosins - metabolism; Protein Interaction Domains and Motifs; Protein Structure, Quaternary; Signal Transduction; TOR Serine-Threonine Kinases - metabolism
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.717

An intramolecular cleft of the FAK FERM domain mediates interaction with sarcomeric myosin. Chemical cross-linking, SAXS and mutational analyses confirm the interaction, and inhibiting the interaction with a peptide activates FAK and promotes the cardiomyocyte hypertrophic response. Focal adhesion kinase (FAK) regulates cellular processes that affect several aspects of development and disease. The FAK N-terminal FERM (4.1 protein–ezrin-radixin-moesin homology) domain, a compact clover-leaf structure, binds partner proteins and mediates intramolecular regulatory interactions. Combined chemical cross-linking coupled to MS, small-angle X-ray scattering, computational docking and mutational analyses showed that the FAK FERM domain has a molecular cleft (∼998 Å 2 ) that interacts with sarcomeric myosin, resulting in FAK inhibition. Accordingly, mutations in a unique short amino acid sequence of the FERM myosin cleft, FP-1, impaired the interaction with myosin and enhanced FAK activity in cardiomyocytes. An FP-1 decoy peptide selectively inhibited myosin interaction and increased FAK activity, promoting cardiomyocyte hypertrophy through activation of the AKT–mammalian target of rapamycin pathway. Our findings uncover an inhibitory interaction between the FAK FERM domain and sarcomeric myosin that presents potential opportunities to modulate the cardiac hypertrophic response through changes in FAK activity.