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
  • 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. [email protected].
  • 10. University of Cincinnati, 231 Albert Sabin Way ML 0524, Cincinnati, OH, 45267, USA. [email protected].
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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