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BMC Biol. 2017 Mar 3;15(1):19. doi: 10.1186/s12915-017-0350-1.

Structural basis for potency differences between GDF8 and GDF11.

Author information

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.

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)

PMID:
28257634
PMCID:
PMC5336696
DOI:
10.1186/s12915-017-0350-1
[Indexed for MEDLINE]
Free PMC Article

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