Groppe Jay, Hinck Cynthia S, Samavarchi-Tehrani Payman, Zubieta Chloe, Schuermann Jonathan P, Taylor Alexander B, Schwarz Patricia M, Wrana Jeffrey L, Hinck Andrew P
Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229, USA.
Mol Cell. 2008 Feb 1;29(2):157-68. doi: 10.1016/j.molcel.2007.11.039.
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-beta3 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.
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源四聚体复合物，以独特的方式跨细胞膜发出信号。与骨形态发生蛋白（BMP）分支的复合物明显因膜定位的亲和力而形成不同，TGF-β复合物通过配体结合的高亲和力（II型）受体对招募低亲和力（I型）受体而协同组装。在这里，我们报告了与两对受体的细胞外结构域复合的TGF-β3的晶体结构，揭示I型受体通过复合配体-II型界面处的独特延伸停靠并被拴系。破坏这些延伸赋予的受体-受体相互作用会消除信号复合物的组装和信号转导（Smad激活）。尽管在结构上相似，但BMP和TGF-β受体以截然不同的模式结合，介导分级和类似开关的组装机制，这些机制可能与细胞质效应器的分支特异性组共同进化。
