Identification of hydropathically complementary putative contact sequences within epidermal growth factor (EGF) and the EGF receptor

Hydropathic complementaries (HC) has been proposed as a novel molecular recognition code for how two proteins can recognize one other and thus form a reversible complex. If a protein contains a segment of a few amino acid residues that is surface-exposed, plus in extended conformation, plus composed of residued whose hydropathy pattern is opposite to that of a correspondingly sized segment on the respective other protein, this protein may bind to the other one through such a segment of HC (1). In order to identify in a pair of proteins sequences of HC we have developed the program PUTATIVE SITES SEARCHER (PSS-1) ∗ (2), a name that alludes to the possibility that such a segment of HC could represent a putative contact “site”. Here we describe the application of PSS-1 to the study of human epidermal growth factor (EGF) and human EGF receptor (EGF-R). Six segments of HC were identified, two of which, designated a and b, fall exactly into experimentally verified contact regions on EGF as well as on EGF-R. Site a consists of residues 25.AEIYMCV.19 of EGF (“half site” a EGF) and of residues 331.NIKHFKN.337 of the EGF-R (“half site” a EGF-R); site b consists of residues 34.VCNCAY.29 of EGF and residues 365.PQELDI.370 of the EGF-R. Most interestingly, both half sites a EGF and b EGF localized in loop B of hEGF which is recognized as being essential for receptor binding. Similar is true for the half sites a EGF-R and b EGF-R that localize in subdomain III (residues 314–445) of the extracellular part of the EGF-R, also identified to be responsible for EGF binding. Thus, each of the two theoretically predicted sites is composed of half sites whose functional importance is experimentally verified. This correspondence supports the principal suitability of PSS-1 and suggests that EGF binds to EGF-R at least in part by means of HC contacts besides using, most probably, also “classical” (i.e. non-HC—type) contacts (e.g. charge interactions or hydrophobic bonds).