Structural basis for potency differences between GDF8 and GDF11

Ryan G. Walker, Magdalena Czepnik, Erich J. Goebel, Jason C. McCoy, Ana Vujic, Miook Cho, Juhyun Oh, Senem Aykul, Kelly L. Walton, Gauthier Schang, Daniel J. Bernard, Andrew P. Hinck, Craig A. Harrison, Erik Martinez-Hackert, Amy J. Wagers, Richard T. Lee, Thomas B. Thompson

Growth/differentiation factor 8 (GDF8) and GDF11 are two highly similar members of the transforming growth factor β (TGFβ) family. While GDF8 has been recognized as a negative regulator of muscle growth and differentiation, there are conflicting studies on the function of GDF11 and whether GDF11 has beneficial effects on age-related dysfunction. To address whether GDF8 and GDF11 are functionally identical, we compared their signaling and structural properties. Here we show that, despite their high similarity, GDF11 is a more potent activator of SMAD2/3 and signals more effectively through the type I activin-like receptor kinase receptors ALK4/5/7 than GDF8. Resolution of the GDF11:FS288 complex, apo-GDF8, and apo-GDF11 crystal structures reveals unique properties of both ligands, specifically in the type I receptor binding site. Lastly, substitution of GDF11 residues into GDF8 confers enhanced activity to GDF8. These studies identify distinctive structural features of GDF11 that enhance its potency, relative to GDF8; however, the biological consequences of these differences remain to be determined.