Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH 45267.
Skeletal Diseases Therapeutic Focus Area, Regeneron Pharmaceuticals, Tarrytown, NY 10591.
Proc Natl Acad Sci U S A. 2019 Jul 30;116(31):15505-15513. doi: 10.1073/pnas.1906253116. Epub 2019 Jul 17.
TGFβ family ligands, which include the TGFβs, BMPs, and activins, signal by forming a ternary complex with type I and type II receptors. For TGFβs and BMPs, structures of ternary complexes have revealed differences in receptor assembly. However, structural information for how activins assemble a ternary receptor complex is lacking. We report the structure of an activin class member, GDF11, in complex with the type II receptor ActRIIB and the type I receptor Alk5. The structure reveals that receptor positioning is similar to the BMP class, with no interreceptor contacts; however, the type I receptor interactions are shifted toward the ligand fingertips and away from the dimer interface. Mutational analysis shows that ligand type I specificity is derived from differences in the fingertips of the ligands that interact with an extended loop specific to Alk4 and Alk5. The study also reveals differences for how TGFβ and GDF11 bind to the same type I receptor, Alk5. For GDF11, additional contacts at the fingertip region substitute for the interreceptor interactions that are seen for TGFβ, indicating that Alk5 binding to GDF11 is more dependent on direct contacts. In support, we show that a single residue of Alk5 (Phe), when mutated, abolishes GDF11 signaling, but has little impact on TGFβ signaling. The structure of GDF11/ActRIIB/Alk5 shows that, across the TGFβ family, different mechanisms regulate type I receptor binding and specificity, providing a molecular explanation for how the activin class accommodates low-affinity type I interactions without the requirement of cooperative receptor interactions.
TGFβ 家族配体包括 TGFβs、BMPs 和激活素，通过与 I 型和 II 型受体形成三元复合物来传递信号。对于 TGFβs 和 BMPs，三元复合物的结构揭示了受体组装的差异。然而，对于激活素如何组装三元受体复合物的结构信息尚不清楚。我们报告了一种激活素类成员 GDF11 与 II 型受体 ActRIIB 和 I 型受体 Alk5 形成复合物的结构。该结构表明，受体定位与 BMP 类相似，没有受体间接触；然而，I 型受体相互作用向配体指尖移动，远离二聚体界面。突变分析表明，配体 I 型特异性源自与 Alk4 和 Alk5 特异性延伸环相互作用的配体指尖的差异。该研究还揭示了 TGFβ 和 GDF11 如何与相同的 I 型受体 Alk5 结合的差异。对于 GDF11，在指尖区域的额外接触替代了 TGFβ 中看到的受体间相互作用，表明 Alk5 与 GDF11 的结合更依赖于直接接触。我们还表明，当突变时，Alk5 的单个残基（苯丙氨酸）会使 GDF11 信号失活，但对 TGFβ 信号几乎没有影响。GDF11/ActRIIB/Alk5 的结构表明，在整个 TGFβ 家族中，不同的机制调节 I 型受体结合和特异性，为激活素类如何在不依赖协同受体相互作用的情况下容纳低亲和力 I 型相互作用提供了分子解释。
