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Force interacts with macromolecular structure in activation of TGF-beta

机译：力与TGF-β激活中的大分子结构相互作用

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摘要

Integrins are adhesion receptors that transmit force across the plasma membrane between extracellular ligands and the actin cytoskeleton. In activation of the transforming growth factor-beta 1 precursor (pro-TGF-beta 1), integrins bind to the prodomain, apply force, and release the TGF-beta growth factor. However, we know little about how integrins bind macromolecular ligands in the extracellular matrix or transmit force to them. Here we show how integrin alpha(V)beta(6) binds pro-TGF-beta 1 in an orientation biologically relevant for force-dependent release of TGF-beta from latency. The conformation of the prodomain integrin-binding motif differs in the presence and absence of integrin binding; differences extend well outside the interface and illustrate how integrins can remodel extracellular matrix. Remodelled residues outside the interface stabilize the integrin-bound conformation, adopt a conformation similar to earlier-evolving family members, and show how macromolecular components outside the binding motif contribute to integrin recognition. Regions in and outside the highly interdigitated interface stabilize a specific integrin/pro-TGF-beta orientation that defines the pathway through these macromolecules which actin-cytoskeleton-generated tensile force takes when applied through the integrin beta-subunit. Simulations of force-dependent activation of TGF-beta demonstrate evolutionary specializations for force application through the TGF-beta prodomain and through the beta- and not alpha-subunit of the integrin.
机译：整联蛋白是粘附力受体，其在细胞外配体和肌动蛋白细胞骨架之间跨质膜传递力。在转化生长因子-β1前体（pro-TGF-beta 1）的激活中，整联蛋白与前域结合，施加作用力并释放TGF-beta生长因子。但是，我们对整联蛋白如何结合细胞外基质中的大分子配体或将力传递给它们的了解甚少。在这里，我们展示了整联蛋白alpha（V）beta（6）如何以与潜伏期依赖于TGF-beta的力依赖性释放生物学相关的方向结合pro-TGF-beta 1。前域整联蛋白结合基序的构象在整联蛋白结合的存在与否方面有所不同。差异延伸到界面外，说明整合素如何重塑细胞外基质。界面外的重塑残基可稳定整合素结合的构象，采用与早期进化的家族成员相似的构象，并显示结合基序外的大分子成分如何促进整合素的识别。高叉指界面内部和外部的区域稳定了特定的整联蛋白/pro-TGF-β方向，该方向定义了通过这些大分子的路径，当通过整联蛋白β亚基施加时，肌动蛋白细胞骨架产生的拉力就会通过。 TGF-β的力依赖性激活的模拟显示了通过TGF-β前结构域和整联蛋白的β-而不是α-亚基施加力的进化专业化。

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  • 来源
    《Nature》 |2017年第7639期|55-59|共5页
  • 作者

    Dong Xianchi; Zhao Bo; Iacob Roxana E.; Zhu Jianghai; Koksal Adem C.; Lu Chafen; Engen John R.; Springer Timothy A.;

  • 作者单位

    Harvard Med Sch, Childrens Hosp Boston, Boston, MA 02115 USA|Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA;

    Harvard Med Sch, Childrens Hosp Boston, Boston, MA 02115 USA|Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA;

    Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA;

    Harvard Med Sch, Childrens Hosp Boston, Boston, MA 02115 USA|Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA;

    Harvard Med Sch, Childrens Hosp Boston, Boston, MA 02115 USA|Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA;

    Harvard Med Sch, Childrens Hosp Boston, Boston, MA 02115 USA|Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA;

    Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA;

    Harvard Med Sch, Childrens Hosp Boston, Boston, MA 02115 USA|Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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