Latent TGF-β structure and activation.
Latent TGF-β structure and activation.
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DOI：
10.1038/nature10152
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发表时间：
2011-06-15
期刊：
影响因子：
64.8
通讯作者：
Springer TA
中科院分区：
文献类型：
--
作者：
Shi M;Zhu J;Wang R;Chen X;Mi L;Walz T;Springer TA
转化生长因子-β是一种与其原结构域形成的潜伏复合体，储存在细胞外基质中。转化生长因子-β1的激活需要αv整合素与原结构域上的RGD域结合，并对该结构域施加作用力，该结构域由潜在的转化生长因子-β结合蛋白保持在细胞外基质中。二聚体猪前转化生长因子-β1的晶体显示了一个环状的复合体，这是一个新的原结构域折叠，并显示了原结构域如何保护生长因子不被受体识别并改变其构象。αvβ6整合素与原结构域之间的复合作用不足以促进β1的释放。依赖于力的激活需要松开包围每个生长因子单体的“紧身衣”，该位置可以被二硫键锁定。所有33个转化生长因子-β家族成员的序列都显示了相似的前域折叠。该结构提供了对生长和分化因子家族的调节的洞察力，这些因子在形态发生和动态平衡中具有基本的重要性。
Transforming growth factor (TGF)-β is stored in the extracellular matrix as a latent complex with its prodomain. Activation of TGF-β1 requires the binding of αv integrin to an RGD sequence in the prodomain and exertion of force on this domain, which is held in the extracellular matrix by latent TGF-β binding proteins. Crystals of dimeric porcine proTGF-β1 reveal a ring-shaped complex, a novel fold for the prodomain, and show how the prodomain shields the growth factor from recognition by receptors and alters its conformation. Complex formation between αvβ6 integrin and the prodomain is insufficient for TGF-β1 release. Force-dependent activation requires unfastening of a ‘straitjacket’ that encircles each growth-factor monomer at a position that can be locked by a disulphide bond. Sequences of all 33 TGF-β family members indicate a similar prodomain fold. The structure provides insights into the regulation of a family of growth and differentiation factors of fundamental importance in morphogenesis and homeostasis.