Modularity in receptor evolution: insulin- and glucagon-like peptide modules as binding sites for insulin and glucose in the insulin receptor
Robert Root-Bernstein1, Jessica Vonck2
1Department of Physiology, Michigan State University, Missouri, USA; 2College of Human Medicine, Michigan State University, Missouri, USA
Abstract: Dwyer suggested that peptide receptors evolved from self-aggregating peptides. Root-Bernstein extended Dwyer’s theory to include complementary molecules. Insulin is a self-aggregating peptide. Insulin is also complementary (and therefore binds) to glucagon. We have shown previously using similarities searches that the insulin receptor (IR) has several insulin-like and several glucagon-like sequences associated with insulin-binding regions. We demonstrate here that peptides derived from these insulin- and glucagon-like regions bind insulin with up to high-nanomolar affinity, providing experimental evidence for the evolution of the IR from insulin- and glucagon-like modules. Moreover, we demonstrate that insulin itself binds glucose (and cytochalasin B), and that many of the insulin-like regions of the IR (but not the glucagon-like regions of the insulin receptor) do likewise. These data suggest the function of insulin, and of the IR in glucose regulation has been directed by chemical selection for their mutual set of molecular interactions. This model may be generalizable to the evolution of other receptor and transporter systems. The relationship between molecular structure and function within living systems may be highly constrained by selection for molecular complementarity.
Keywords: co-evolution, modular evolution, molecular complementarity, chemical selection, molecular paleontology
This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.Download Article [PDF]