Molecular basis of ALK1-mediated signalling by BMP9/BMP10 and their prodomain-bound forms
Molecular basis of ALK1-mediated signalling by BMP9/BMP10 and their prodomain-bound forms
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DOI：
10.1038/s41467-020-15425-3
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发表时间：
2020-04-01
影响因子：
16.6
通讯作者：
Li, Wei
中科院分区：
文献类型：
--
作者：
Salmon, Richard M.;Guo, Jingxu;Li, Wei
激活素受体样激酶1（ALK 1）介导的内皮细胞信号传导对骨形态发生蛋白9（BMP 9）和BMP 10的响应在心血管疾病和癌症中具有重要意义。然而，ALK 1介导的信号传导的详细分子机制仍不清楚。在这里，我们报告了BMP 10：ALK 1复合物在2.3 A和前结构域结合的BMP 9：ALK 1复合物在3.3 A的晶体结构。结构分析揭示了一种三方识别机制，该机制定义了BMP 9和BMP 10对ALK 1的特异性，并预测crossveinless 2不是BMP 9的抑制剂，这一点已被实验证据证实。将BMP 10特异性残基引入BMP 9产生BMP 10样配体，其在C2C12细胞中具有减弱的信号传导活性，验证了三方机制。C2C12中成骨信号传导的丧失在体内不会转化为非成骨活性，并且BMP 10也诱导骨形成。总的来说，这些数据提供了对ALK 1介导的BMP 9和BMP 10信号传导的深入了解，促进了这一重要途径的治疗靶向。
Activin receptor-like kinase 1 (ALK1)-mediated endothelial cell signalling in response to bone morphogenetic protein 9 (BMP9) and BMP10 is of significant importance in cardiovascular disease and cancer. However, detailed molecular mechanisms of ALK1-mediated signalling remain unclear. Here, we report crystal structures of the BMP10:ALK1 complex at 2.3 A and the prodomain-bound BMP9:ALK1 complex at 3.3 A. Structural analyses reveal a tripartite recognition mechanism that defines BMP9 and BMP10 specificity for ALK1, and predict that crossveinless 2 is not an inhibitor of BMP9, which is confirmed by experimental evidence. Introduction of BMP10-specific residues into BMP9 yields BMP10-like ligands with diminished signalling activity in C2C12 cells, validating the tripartite mechanism. The loss of osteogenic signalling in C2C12 does not translate into non-osteogenic activity in vivo and BMP10 also induces bone-formation. Collectively, these data provide insight into ALK1-mediated BMP9 and BMP10 signalling, facilitating therapeutic targeting of this important pathway.