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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

FERM domain interaction with myosin negatively regulates FAK in cardiomyocyte hypertrophy

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Santos, Aline M. [1, 2] ; Schechtman, Deborah [3] ; Cardoso, Alisson C. [2, 1] ; Clemente, Carolina F. M. Z. [1] ; Silva, Julio C. [1] ; Fioramonte, Mariana [4] ; Pereira, Michelle B. M. [2, 1] ; Marin, Talita M. [2, 1] ; Oliveira, Paulo S. L. [1] ; Figueira, Ana Carolina M. [1] ; Oliveira, Saulo H. P. [1] ; Torriani, Iris L. [1, 5] ; Gozzo, Fabio C. [4] ; Neto, Jose Xavier [1] ; Franchini, Kleber G. [1, 2]
Total Authors: 15
[1] Brazilian Assoc Synchrotron Light Technol, Brazilian Natl Lab Biosci, Campinas, SP - Brazil
[2] Univ Estadual Campinas, Sch Med, Dept Internal Med, Campinas, SP - Brazil
[3] Univ Sao Paulo, Inst Chem, Dept Biochem, Sao Paulo - Brazil
[4] Univ Estadual Campinas, Inst Chem, Campinas, SP - Brazil
[5] Univ Estadual Campinas, Gleb Wataghin Phys Inst, Campinas, SP - Brazil
Total Affiliations: 5
Document type: Journal article
Source: Nature Chemical Biology; v. 8, n. 1, p. 102-110, JAN 2012.
Web of Science Citations: 14

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 (similar to 998 angstrom(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. (AU)

FAPESP's process: 06/54878-3 - Pathogenesis of cardiac hypertrophy and failure: mechanisms activated by mechanical stress
Grantee:Kleber Gomes Franchini
Support type: Research Projects - Thematic Grants
FAPESP's process: 10/02628-9 - Cross-linking coupled to mass spectrometry: FERM/Miosin complex interaction mapping
Grantee:Mariana Fioramonte
Support type: Scholarships in Brazil - Master
FAPESP's process: 08/57805-2 - Institute of Bioanalytics
Grantee:Lauro Tatsuo Kubota
Support type: Research Projects - Thematic Grants