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Ternary structure of GDF11 bound to ActRIIB-ECD and Alk5-ECD
Structural highlights
FunctionGDF11_HUMAN Secreted signal that acts globally to specify positional identity along the anterior/posterior axis during development. Play critical roles in patterning both mesodermal and neural tissues and in establishing the skeletal pattern. Publication Abstract from PubMedTGFbeta family ligands, which include the TGFbetas, BMPs, and activins, signal by forming a ternary complex with type I and type II receptors. For TGFbetas 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 TGFbeta 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 TGFbeta, 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 TGFbeta signaling. The structure of GDF11/ActRIIB/Alk5 shows that, across the TGFbeta 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. Structural characterization of an activin class ternary receptor complex reveals a third paradigm for receptor specificity.,Goebel EJ, Corpina RA, Hinck CS, Czepnik M, Castonguay R, Grenha R, Boisvert A, Miklossy G, Fullerton PT, Matzuk MM, Idone VJ, Economides AN, Kumar R, Hinck AP, Thompson TB Proc Natl Acad Sci U S A. 2019 Jul 17. pii: 1906253116. doi:, 10.1073/pnas.1906253116. PMID:31315975[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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