title: Structural basis for potency differences between GDF8 and GDF11.
abstract: 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.
authors.affiliation: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH, 45267, USA.
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Walker
authors.affiliation: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH, 45267, USA.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Czepnik
authors.affiliation: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH, 45267, USA.
authors.forename: Erich J
authors.initials: EJ
authors.lastname: Goebel
authors.affiliation: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH, 45267, USA.
authors.forename: Jason C
authors.initials: JC
authors.lastname: McCoy
authors.affiliation: Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Vujic
authors.affiliation: Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA.|Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Miook
authors.initials: M
authors.lastname: Cho
authors.affiliation: Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA.|Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Juhyun
authors.initials: J
authors.lastname: Oh
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824, USA.
authors.forename: Senem
authors.initials: S
authors.lastname: Aykul
authors.affiliation: Hudson Institute of Medical Research, Clayton, Australia.|Department of Physiology, Monash University, Clayton, Australia.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Walton
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, Quebec, Canada.
authors.forename: Gauthier
authors.initials: G
authors.lastname: Schang
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, Quebec, Canada.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Bernard
authors.affiliation: Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15260, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Hinck
authors.affiliation: Hudson Institute of Medical Research, Clayton, Australia.|Department of Physiology, Monash University, Clayton, Australia.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Harrison
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Martinez-Hackert
authors.affiliation: Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA.|Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagers
authors.affiliation: Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lee
authors.affiliation: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH, 45267, USA. Tom.Thompson@uc.edu.|University of Cincinnati, 231 Albert Sabin Way ML 0524, Cincinnati, OH, 45267, USA. Tom.Thompson@uc.edu.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Thompson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D038681:Follistatin / Q000378:metabolism; D017930:Genes, Reporter; D055412:Growth Differentiation Factors / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D032446:Myoblasts / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D055435:Myostatin / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship
chemical_list: D019485:Bone Morphogenetic Proteins; D038681:Follistatin; C492266:GDF11 protein, human; D055412:Growth Differentiation Factors; D008024:Ligands; D055435:Myostatin; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
keywords: Ligands; Myostatin; Receptor; Structure; Transforming growth factor β (TGFβ)