Structural basis for potency differences between GDF8 and GDF11.


Type
Article
Change log
Authors
Walker, Ryan G 
Czepnik, Magdalena 
Goebel, Erich J 
McCoy, Jason C 
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.

Description
Keywords
Ligands, Myostatin, Receptor, Structure, Transforming growth factor β (TGFβ), Amino Acid Sequence, Animals, Bone Morphogenetic Proteins, Cells, Cultured, Crystallography, X-Ray, Follistatin, Genes, Reporter, Growth Differentiation Factors, Humans, Injections, Intravenous, Ligands, Luciferases, Mice, Models, Molecular, Myoblasts, Myocardium, Myostatin, Phosphorylation, Protein Binding, Protein Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type I, Receptors, Transforming Growth Factor beta, Sequence Alignment, Signal Transduction, Smad Proteins, Structural Homology, Protein, Structure-Activity Relationship
Journal Title
BMC Biol
Conference Name
Journal ISSN
1741-7007
1741-7007
Volume Title
15
Publisher
Springer Science and Business Media LLC