Structural characterization of an activin class ternary receptor complex reveals a third paradigm for receptor specificity.

ABSTRACT: TGF? family ligands, which include the TGF?s, BMPs, and activins, signal by forming a ternary complex with type I and type II receptors. For TGF?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? 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?, indicating that Alk5 binding to GDF11 is more dependent on direct contacts. In support, we show that a single residue of Alk5 (Phe84), when mutated, abolishes GDF11 signaling, but has little impact on TGF? signaling. The structure of GDF11/ActRIIB/Alk5 shows that, across the TGF? 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.

SUBMITTER: Goebel EJ 

PROVIDER: S-EPMC6681762 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature