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Cho, Miook

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Cho, Miook

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    Structural basis for potency differences between GDF8 and GDF11
    (BioMed Central, 2017) Walker, Ryan G.; Czepnik, Magdalena; Goebel, Erich J.; McCoy, Jason C.; Vujic, Ana; Cho, Miook; Oh, Juhyun; Aykul, Senem; Walton, Kelly L.; Schang, Gauthier; Bernard, Daniel J.; Hinck, Andrew P.; Harrison, Craig A.; Martinez-Hackert, Erik; Wagers, Amy; Lee, Richard; Thompson, Thomas B.
    Background: 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. Results: 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. Conclusions: 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. Electronic supplementary material The online version of this article (doi:10.1186/s12915-017-0350-1) contains supplementary material, which is available to authorized users.