Li Ang, Guo Qiang, Wei Ailin, Zhou Yaliang, Hu Weiming
Department of Pancreatic Surgery, West China Hospital, Sichuan University, 37 Guoxue Rd, Chengdu, Sichuan Province, China.
Department of Vascular Surgery, West China Hospital, Sichuan University, 37 Guoxue Rd, Chengdu, Sichuan Province, China.
Cell Biochem Biophys. 2017 Mar;75(1):79-86. doi: 10.1007/s12013-017-0781-x. Epub 2017 Jan 18.
Increases in ligand binding to cellular integrins (activation) play an important role in platelet and leukocyte function. Talin is necessary in vivo and sufficient in vitro for integrin αIIbβ3 activation. The precise mechanisms by which talin activates integrin are still being elucidated. In particular, talin undergoes conformational changes (around the F3 helix) and inserts the F3 helix into lipid bilayer; however, the connection between this lipid-inserting mechanism of talin and talin's capacity to activate integrin has never been explored before. In this work, we used rational mutagenesis, modeled cell systems, and structural modeling to study the potential role of membrane-induced talin conformational changes in talin-mediated integrin activation. Mutations of the residues critical for talin F3 helix to insert into membrane completely abolished talin-mediated integrin activation without affecting the binding of talin to integrins. Furthermore, mutations of the lipid-binding sequences in talin F3 helix significantly reduced the capacity of talin to activate integrin. Our results suggest that the F3 helix may contribute to talin-mediated integrin activation.
配体与细胞整合素结合的增加（激活）在血小板和白细胞功能中起重要作用。在体内，踝蛋白是必需的，在体外，它足以激活整合素αIIbβ3。踝蛋白激活整合素的确切机制仍在阐明之中。特别是，踝蛋白会发生构象变化（围绕F3螺旋）并将F3螺旋插入脂质双层；然而，踝蛋白的这种脂质插入机制与踝蛋白激活整合素的能力之间的联系此前从未被探索过。在这项研究中，我们使用了合理诱变、模拟细胞系统和结构建模来研究膜诱导的踝蛋白构象变化在踝蛋白介导的整合素激活中的潜在作用。对踝蛋白F3螺旋插入膜至关重要的残基的突变完全消除了踝蛋白介导的整合素激活，而不影响踝蛋白与整合素的结合。此外，踝蛋白F3螺旋中脂质结合序列的突变显著降低了踝蛋白激活整合素的能力。我们的结果表明，F3螺旋可能有助于踝蛋白介导的整合素激活。
