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Structure-function relationships for the EGF/TGF-alpha family of mitogens
L C Groenen1, E C Nice, A W Burgess
1Ludwig Institute for Cancer Research, PO Royal Melbourne Hospital, Australia.
Growth Factors (Chur, Switzerland)
|January 1, 1994
Summary
Epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha) are key ligands for the EGF-receptor. Structure-function studies reveal Arg41 is critical for binding, suggesting complex antagonists are unlikely from short peptides.
Area of Science:
- Molecular biology
- Biochemistry
- Cell signaling
Background:
- Epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha) are mitogenic ligands for the EGF-receptor.
- TGF-alpha is implicated as an autocrine growth factor in various cancer cell lines.
Purpose of the Study:
- To review structure-function relationships of EGF/TGF-alpha.
- To correlate findings with the 3D structure of EGF/TGF-alpha.
- To discuss challenges in developing EGF/TGF-alpha analogues.
Main Methods:
- Review of structure-function studies on EGF/TGF-alpha.
- Analysis of binding data and biological assays.
- Correlation with three-dimensional structural information.
Main Results:
- Binding data suggest a receptor interaction surface on one side of EGF/TGF-alpha.
- Arg41 and Leu47 are identified as key binding determinants.
- Arg41 is critical, requiring its full hydrogen-bonding capacity for receptor binding.
Conclusions:
- The receptor interaction surface involves residues from both N- and C-terminal domains.
- Developing agonists or antagonists from short peptides is unlikely.
- Difficulties in analogue purification and assays may explain contradictory results.