Structural Basis for a Functional Antagonist in the Transforming Growth Factor β Superfamily

Within the transforming growth factor β superfamily, the agonist-antagonist relationship between activin and inhibin is unique and critical to integrated reproductive function. Activin acts in the pituitary to stimulate follicle-stimulating hormone, and is antagonized by endocrine acting, gonadally...

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Bibliographic Details
Published in:The Journal of biological chemistry 2005-12, Vol.280 (48), p.40177-40186
Main Authors: Cook, Robert W., Thompson, Thomas B., Kurup, Sudhi P., Jardetzky, Theodore S., Woodruff, Teresa K.
Format: Article
Language:English
Subjects:
Activin Receptors - chemistry
Activins - antagonists & inhibitors
Activins - chemistry
Amino Acid Sequence
Animals
Binding, Competitive
Blotting, Western
Chlorocebus aethiops
CHO Cells
COS Cells
Cricetinae
DNA Mutational Analysis
Glycosylation
Immunoprecipitation
Inhibin-beta Subunits - chemistry
Inhibins - chemistry
Ligands
Luciferases - metabolism
Microscopy, Fluorescence
Models, Molecular
Molecular Sequence Data
Multigene Family
Mutagenesis
Mutation
Phosphorylation
Plasmids - metabolism
Protein Binding
Protein Conformation
Protein Structure, Tertiary
Signal Transduction
Smad3 Protein - metabolism
Transforming Growth Factor beta - antagonists & inhibitors
Transforming Growth Factor beta - chemistry
Transforming Growth Factor beta - physiology
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Summary:Within the transforming growth factor β superfamily, the agonist-antagonist relationship between activin and inhibin is unique and critical to integrated reproductive function. Activin acts in the pituitary to stimulate follicle-stimulating hormone, and is antagonized by endocrine acting, gonadally derived inhibin. We have undertaken a mutational analysis of the activin βA subunit to determine the precise structural aspects that contribute to inhibin antagonism of activin. By substituting specific amino acid residues in the activin βA subunit with similarly aligned amino acids from the α subunit, we have pinpointed the residues required for activin receptor binding and activity, as well as for inhibin antagonism of activin through its receptors. Additionally, we have identified an activin mutant with a higher affinity for the activin type I receptor that provides structural evidence for the evolution of ligand-receptor interactions within the transforming growth factor β superfamily.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M504591200