Structure of the ternary signaling complex of a TGF-β superfamily member
Structure of the ternary signaling complex of a TGF-β superfamily member
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DOI：
10.1073/pnas.0602558103
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发表时间：
2006-05-16
影响因子：
11.1
通讯作者：
Choe, Senyon
中科院分区：
文献类型：
--
作者：
Allendorph, George P.;Vale, Wylie W.;Choe, Senyon
骨形态发生蛋白2（BMP - 2）与其I型受体[骨形态发生蛋白受体Ia型（BMPR - Ia） - 胞外域（ECD）]和II型受体[激活素受体II型（ActRII） - 胞外域]之间形成的完整信号复合物的晶体结构显示了受体组装的两个基本结构限制。首先，同源二聚体BMP - 2配体对称地组装两对每种受体，其中每种受体的胞外域并不发生物理接触。因此，受体胞外域之间如果存在构象信息传递，应该是通过中心配体进行的。其次，该复合物的I型和II型受体界面，与诸如BMP - 2/BMPR Ia - ECD、BMP - 7/ActRII - ECD和激活素/ActRIIb - ECD等二元复合物的相应界面相比，表明配体和受体都重复使用一些常见的位置组合。因此，受体界面上决定特异性的氨基酸差异也应该能够解释单个受体对不同配体亚基亲和力的差异。我们发现BMP - 2的一个特定突变使其对ActRII - ECD的亲和力提高了5倍。这些结果共同表明，特定的信号输出在很大程度上由两个变量决定，即配体 - 受体对的特性以及相关受体以膜限制的方式受配体灵活性控制的协同组装模式。
The crystal structure of the complete signaling complex formed between bone morphogenetic protein 2 (BMP-2) and the extracellular domains (ECDs) of its type I receptor [bone morphogenetic protein receptor type la (BMPR-la)-ECD] and its type 11 receptor [activin receptor type 11 (ActRII)-ECD] shows two fundamental structural constraints for receptor assembly. First, the homodimeric BMP-2 ligand assembles two pairs of each receptor symmetrically, where each of the receptor ECDs does not make physical contact. Therefore, conformational communication between receptor ECDs, if any, should be propagated through the central ligand. Second, the type I and 11 receptor interfaces of the complex, when compared with those of binary complexes such as BMP-2/BMPR Ia-ECD, BMP-7/ActRII-ECD, and activin/ActRIIb-ECD, respectively, show there are common sets of positions repeatedly used by both ligands and receptors. Therefore, specificity-determining amino acid differences at the receptor interfaces should also account for the disparity in affinity of individual receptors for different ligand subunits. We find that a specific mutation to BMP-2 increases its affinity to ActRII-ECD by 5-fold. These results together establish that the specific signaling output is largely determined by two variables, the ligand-receptor pair identity and the mode of cooperative assembly of relevant receptors governed by the ligand flexibility in a membrane-restricted manner.