2. Academic Validation
  3. Structural basis for potency differences between GDF8 and GDF11

Structural basis for potency differences between GDF8 and GDF11

  • BMC Biol. 2017 Mar 3;15(1):19. doi: 10.1186/s12915-017-0350-1.
Ryan G Walker 1,  Magdalena Czepnik 1,  Erich J Goebel 1,  Jason C McCoy 1,  Ana Vujic 2,  Miook Cho 2 3,  Juhyun Oh 2 3,  Senem Aykul 4,  Kelly L Walton 5 6,  Gauthier Schang 7,  Daniel J Bernard 7,  Andrew P Hinck 8,  Craig A Harrison 5 6,  Erik Martinez-Hackert 4,  Amy J Wagers 2 3,  Richard T Lee 2,  Thomas B Thompson 9 10
Affiliations

Affiliations

  • 1 Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH, 45267, USA.
  • 2 Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA.
  • 3 Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA, 02115, USA.
  • 4 Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824, USA.
  • 5 Hudson Institute of Medical Research, Clayton, Australia.
  • 6 Department of Physiology, Monash University, Clayton, Australia.
  • 7 Department of Pharmacology and Therapeutics, McGill University, Montréal, Quebec, Canada.
  • 8 Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15260, USA.
  • 9 Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH, 45267, USA. Tom.Thompson@uc.edu.
  • 10 University of Cincinnati, 231 Albert Sabin Way ML 0524, Cincinnati, OH, 45267, USA. Tom.Thompson@uc.edu.
PMID: 28257634 DOI: 10.1186/s12915-017-0350-1
Abstract

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.

Keywords

Ligands; Myostatin; Receptor; Structure; Transforming growth factor β (TGFβ).

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