Structural characterization of an activin class ternary receptor complex reveals a third paradigm for receptor specificity
Structural characterization of an activin class ternary receptor complex reveals a third paradigm for receptor specificity
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DOI：
10.1073/pnas.1906253116
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发表时间：
2019-07-30
影响因子：
11.1
通讯作者：
Thompson, Thomas B.
中科院分区：
文献类型：
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作者：
Goebel, Erich J.;Corpina, Richard A.;Thompson, Thomas B.
TGF β家族配体，包括TGF β 5、bmp和激活素，通过与I型和II型受体形成三元配合物来传递信号。对于TGF β 5和bmp，三元复合物的结构显示了受体组装的差异。然而，关于激活素如何组装三元受体复合物的结构信息是缺乏的。我们报道了激活素类成员GDF11与II型受体ActRIIB和I型受体Alk5复合物的结构。结构表明，受体定位与BMP类相似，没有受体间接触；然而，I型受体的相互作用转移到配体的指尖，远离二聚体界面。突变分析表明，I型配体特异性来源于与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TGF β和GDF11与相同的I型受体Alk5结合方式的差异。对于GDF11，指尖区域的额外接触取代了TGF β的受体间相互作用，表明Alk5与GDF11的结合更依赖于直接接触。为了支持这一观点，我们发现Alk5的单个残基（Phe(84)）发生突变时，会消除GDF11信号，但对TGF β信号传导几乎没有影响。GDF11/ActRIIB/Alk5的结构表明，在整个TGF β家族中，不同的机制调节I型受体的结合和特异性，这为激活素类如何在不需要协同受体相互作用的情况下适应低亲和力的I型相互作用提供了分子解释。
TGF beta family ligands, which include the TGF beta s, BMPs, and activins, signal by forming a ternary complex with type I and type II receptors. For TGF beta s 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 TGF beta 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 TGF beta, indicating that Alk5 binding to GDF11 is more dependent on direct contacts. In support, we show that a single residue of Alk5 (Phe(84)), when mutated, abolishes GDF11 signaling, but has little impact on TGF beta signaling. The structure of GDF11/ActRIIB/Alk5 shows that, across the TGF beta 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.