Three-Dimensional Structural Models for EGF and Insulin Receptor Interactions and Signal Transduction
Several hormones and growth factors are known to activate their cellular signalling through a receptor tyrosine kinase (RTK). These receptors have similar molecular structures: a large cystine-rich, extracellular ligand binding domain, a single hydrophobic transmembrane helix and a cytoplasmic tyrosine kinase. They can be divided into three subclasses. The first of these includes the EGF and TGFα receptor and the neu (also called HER-2 or C-erb-B) proto-oncogene; these are closely related to the viral oncogene v-erb-B. The second class includes the receptors for insulin and IGF1; these are synthesised as a single peptide chain, processed into a-and B-chains and exist in the native state as covalently bound dimers. The third subclass includes receptors for PDGF and CSF-1 and related oncogene products v-fms and c-kit. The primary structures and functions of these three subclasses have been reviewed by Carpenter (1987) and by Yarden and Ullrich (1988). The ligands for all these receptors are cystine rich polypeptides of sufficient size to assume a globular structure. Considerable information is available on the conformations of insulin and EGF from X-ray diffraction and nuclear magnetic resonance experiments, and so some speculation can now be made on receptor interactions. Here, we review evidence for the three-dimensional structures of the ligands - hormones and growth factors - and the receptor tyrosine kinases for the EGF and insulin subclasses. We consider both experimental evidence and conclusions based on knowledge-based modelling procedures. We then discuss the implications for hormone receptor interactions and for signal transduction leading to activation of the cytoplasmic tyrosine kinase.
KeywordsCrystallization Tyrosine Glycine Lysine Oligomer
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