The significance of Valine 33 as a ligand-specific epitope of transforming growth factor ?

Puddicombe, Sarah M., Chamberlin, Stephen G., Macgarvie, Jennie, Richter, Audrey, Drummond, Douglas R., Collins, Jane, Wood, Lynn and Davies, Donna E. (1996) The significance of Valine 33 as a ligand-specific epitope of transforming growth factor ? The Journal of Biological Chemistry, 271 (26), 15367-15372. (doi:10.1074/jbc.271.26.15367). (PMID:8663070)

Abstract

Although binding of epidermal growth factor (EGF) and transforming growth factor ? (TGF?) to the EGF receptor (EGFR) is mutually competitive, their binding is not identical, and their biological activities are not always equivalent. To probe for ligand-specific interactions, we have synthesized analogues of TGF? with modifications to the residue lying between the fourth and fifth cysteines (the “hinge”). Although this residue lies in a structurally conserved region of the protein, it is not conserved within the EGFR ligand family. Our results show that in TGF? there is a preference for a bulky hydrophobic hinge residue; this contrasts with EGF, for which a hydrogen bond donor functionality is preferred. Sequence analysis of the human EGFR ligands revealed that the nature of the hinge residue correlated with the sequence in the B-loop ?-sheet. As this region is an important determinant in recognition of TGF? by the chicken EGFR, we assessed the mitogenicity of the TGF? hinge mutants, as well as the other EGFR ligands, using chicken embryo fibroblasts. The preference of the chicken EGFR for TGF? hinge mutants with hydrophobic side chains paralleled that of the human EGFR. Betacellulin and heparin-binding EGF-like growth factor also possess an hydrophobic hinge; both were at least as potent as TGF? for chicken embryo fibroblasts. EGF and amphiregulin, both with hydrogen bond donor functionalities at their hinge, displayed markedly decreased in potency by comparison with TGF?. We propose that EGFR ligands can be subclassified into TGF?-like and EGF-like and that this is of functional significance, identifying a potential mechanism whereby EGFR can discriminate between its ligands.

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Contributors

Author: Donna E. Davies

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