Structural basis for a functional antagonist in the transforming growth factor beta superfamily.
Within the transforming growth factor beta 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 betaA subunit to determine the precise structural aspects that contribute to inhibin antagonism of activin. By substituting specific amino acid residues in the activin betaA subunit with similarly aligned amino acids from the alpha 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 beta superfamily.
Cook
Robert W
RW
Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208, USA.
Thompson
Thomas B
TB
Kurup
Sudhi P
SP
Jardetzky
Theodore S
TS
Woodruff
Teresa K
TK
D029404:Activin Receptors / Q000737:chemistry; D028341:Activins / Q000037:antagonists & inhibitors / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D015153:Blotting, Western; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004252:DNA Mutational Analysis; D006031:Glycosylation; D047468:Immunoprecipitation; D028322:Inhibin-beta Subunits / Q000737:chemistry; D007265:Inhibins / Q000737:chemistry; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family; D016296:Mutagenesis; D009154:Mutation; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology*
D008024:Ligands; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C422405:activin A; C422362:inhibin A; C103008:inhibin beta A subunit; D028341:Activins; D007265:Inhibins; D028322:Inhibin-beta Subunits; D008156:Luciferases; D029404:Activin Receptors