Cooperative assembly of TGF-β superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding
Cooperative assembly of TGF-β superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding
复制标题
DOI：
10.1016/j.molcel.2007.11.039
复制
发表时间：
2008-02-01
期刊：
影响因子：
16
通讯作者：
Hinck, Andrew P.
中科院分区：
文献类型：
--
作者：
Groppe, Jay;Hinck, Cynthia S.;Hinck, Andrew P.
转化生长因子- β (tgf - β)超家族的二聚体配体通过组装结构相关的丝氨酸/苏氨酸激酶受体对的异四聚体复合物以独特的方式穿过细胞膜。骨形态发生蛋白（BMP）分支的复合物显然是由于膜定位而形成的，而tgf - β复合物是通过配体结合的高亲和力（II型）对募集低亲和力（I型）受体来协同组装的。在这里，我们报道了tgf - β 3与这两对受体的细胞外结构域复合物的晶体结构，揭示了I型对接并通过在复合配体- II型界面上的独特延伸而被束缚。破坏这些延伸所带来的受体-受体相互作用会破坏信号复合体的组装和信号转导（Smad激活）。虽然结构相似，但BMP和tgf - β受体的结合方式却截然不同，介导的渐变和开关样组装机制可能与细胞质效应物的分支特异性群体共同进化。
Dimeric ligands of the transforming growth factor-beta (TGF-beta) superfamily signal across cell membranes in a distinctive manner by assembling heterotetrameric complexes of structurally related serine/threonine-kinase receptor pairs. Unlike complexes of the bone morphogenetic protein (BMP) branch that apparently form due to avidity from membrane localization, TGF-beta complexes assemble cooperatively through recruitment of the low-affinity (type I) receptor by the ligand-bound high-affinity (type II) pair. Here we report the crystal structure of TGF-beta 3 in complex with the extracellular domains of both pairs of receptors, revealing that the type I docks and becomes tethered via unique extensions at a composite ligand-type II interface. Disrupting the receptor-receptor interactions conferred by these extensions abolishes assembly of the signaling complex and signal transduction (Smad activation). Although structurally similar, BMP and TGF-beta receptors bind in dramatically different modes, mediating graded and switch-like assembly mechanisms that may have coevolved with branch-specific groups of cytoplasmic effectors.