STRUCTURE-FUNCTION-RELATIONSHIPS FOR THE EGF TGF-ALPHA FAMILY OF MITOGENS/

Epidermal growth factor (EGF) and transforming growth factor alpha (TG F-alpha) are ligands for the EGF-receptor and act as mitogens for a va riety of tissues. TGF-alpha, in particular, has been implicated as an autocrine growth factor for several cancer cell lines. Over the last 1 0 years many groups have examined the structure-function relationships in EGF/TGF-alpha in attempts to develop antagonists or agonists. In t his review the results of these studies are summarised and related to the three-dimensional structure of EGF/TGF-alpha. The difficulties ass ociated with the purification and characterisation of analogues of EGF /TGF-alpha and with the biological assays are discussed. It is clear t hat these difficulties have, in some cases, led to apparently contradi cting results. The available binding data indicate that the receptor i nteraction surface for EGF/TGF-alpha might encompass one complete side of the molecule with a few strong binding determinants, in particular Arg41 and Leu47. The arginine at position 41 is the most critical res idue and its full hydrogen-bonding capacity is needed for strong bindi ng of EGF/TGF-alpha to the EGF-receptor. As this side of the molecule consists of residues from both the N- and C-terminal domain, it seems unlikely that agonists or antagonists can be developed on the basis of short peptides taken from the primary sequence. This concept is suppo rted by the available binding and activity data.