Structural determinants of binding and specificity in transforming growth factor-receptor interactions.
Transforming growth factor (TGF-beta) protein families are cytokines that occur as a large number of homologous proteins. Three major subgroups of these proteins with marked specificities for their receptors have been found-TGF-beta, activin/inhibin, and bone morphogenic protein. Although structural information is available for some members of the TGF-beta family of ligands and receptors, very little is known about the way these growth factors interact with the extracellular domains of their cell surface receptors, especially the type II receptor. In addition, the elements that are the determinants of binding and specificity of the ligands are poorly understood. The structure of the extracellular domain of the receptor is a three-finger fold similar to some toxin structures. Amino acid exchanges between multiply aligned homologous sequences of type II receptors point to a residue at the surface, specifically finger 1, as the determinant of ligand specificity and complex formation. The "knuckle" epitope of ligands was predicted to be the surface that interacts with the type II receptor. The residues on strands beta2, beta3, beta7, beta8 and the loop region joining beta2 and beta3 and joining beta7 and beta8 of the ligands were identified as determinants of binding and specificity. These results are supported by studies on the docking of the type II receptor to the ligand dimer-type I receptor complex.
Shah
P K
PK
National Centre for Biological Sciences, UAS-GKVK Campus, Bangalore, India.
Buslje
C M
CM
Sowdhamini
R
R
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019143:Evolution, Molecular; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D013379:Substrate Specificity; D016212:Transforming Growth Factor beta / Q000737:chemistry* / Q000378:metabolism
D008024:Ligands; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II