Department of Internal Medicine, School of Medicine, University of Campinas, Campinas, São Paulo, Brazil.
Nat Chem Biol. 2011 Nov 20;8(1):102-10. doi: 10.1038/nchembio.717.
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.
黏着斑激酶 (FAK) 调节细胞过程，这些过程影响发育和疾病的几个方面。FAK N 端 FERM（4.1 蛋白-埃兹蛋白- radixin-moesin 同源）域是一种紧凑的三叶草结构，与伴侣蛋白结合并介导分子内调节相互作用。结合化学交联和 MS、小角度 X 射线散射、计算对接和突变分析表明，FAK FERM 结构域具有一个分子裂缝（~998 Å(2)），与肌球蛋白相互作用，导致 FAK 抑制。因此，FERM 肌球蛋白裂缝中独特的短氨基酸序列 FP-1 中的突变会损害与肌球蛋白的相互作用，并增强心肌细胞中的 FAK 活性。FP-1 诱饵肽选择性抑制肌球蛋白相互作用并增加 FAK 活性，通过激活 AKT-雷帕霉素靶蛋白通路促进心肌细胞肥大。我们的发现揭示了 FAK FERM 结构域与肌球蛋白之间的抑制相互作用，为通过改变 FAK 活性来调节心脏肥厚反应提供了潜在的机会。
