Structural basis for potency differences between GDF8 and GDF11

BMC Biology

Research Article

Senem Aykul¹  Erik Martinez-Hackert¹  Erich J. Goebel²  Ryan G. Walker²  Jason C. McCoy²  Magdalena Czepnik²  Thomas B. Thompson³  Gauthier Schang⁴  Daniel J. Bernard⁴  Andrew P. Hinck⁵  Ana Vujic⁶  Richard T. Lee⁶  Miook Cho⁷  Juhyun Oh⁷  Amy J. Wagers⁷  Craig A. Harrison⁸  Kelly L. Walton⁸ 

[1] Department of Biochemistry and Molecular Biology, Michigan State University, 48824, East Lansing, MI, USA;Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, 45267, Cincinnati, OH, USA;Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, 45267, Cincinnati, OH, USA;University of Cincinnati, 231 Albert Sabin Way ML 0524, 45267, Cincinnati, OH, USA;Department of Pharmacology and Therapeutics, McGill University, Montréal, Quebec, Canada;Department of Structural Biology, University of Pittsburgh School of Medicine, 15260, Pittsburgh, PA, USA;Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology, Harvard University, 02138, Cambridge, MA, USA;Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology, Harvard University, 02138, Cambridge, MA, USA;Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, 02115, Boston, MA, USA;Hudson Institute of Medical Research, Clayton, Australia;Department of Physiology, Monash University, Clayton, Australia;

关键词: Ligands;    Myostatin;    Receptor;    Structure;    Transforming growth factor β (TGFβ);   

DOI  :  10.1186/s12915-017-0350-1

 received in 2016-11-21, accepted in 2017-01-18,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundGrowth/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.ResultsHere 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.ConclusionsThese 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.

【 授权许可】

CC BY   
© Thompson et al. 2017