Insulin and its receptor: structure, function and evolution

Abstract

I present here a personal perspective on more than three decades of research into the structural biology of the insulin-receptor interaction. The solution of the three-dimensional structure of insulin in 1969 provided a detailed understanding of the insulin surfaces involved in self-assembly. In subsequent years, hundreds of insulin analogues were prepared by insulin chemists and molecular biologists, with the goal of relating the structure to the biological function of the molecule. The design of methods for direct receptor-binding studies in the 1970s, and the cloning of the receptor in the mid 1980s, provided the required tools for detailed structure-function studies. In the absence of a full three-dimensional structure of the insulin-receptor complex, I attempt to assemble the existing pieces of the puzzle generated by our and other laboratories, in order to generate a plausible mechanistic model of the insulin-receptor interaction that explains its kinetics and negative cooperativity.

An insulin-like peptide regulates egg maturation and metabolism in the mosquito Aedes aegypti

“…Essential residues implicated in insulin binding to the IR include Gly-1, Gln-5, Tyr-19, and Asn-21 on the A chain and Tyr-16, Gly 23, Phe-24, Phe-25, and Tyr-26 (GFFY motif) on the B chain that together form the ''classical binding surface'' (Fig. 1 A) (2,(20)(21)(22). Other important residues include IleA2 and ValA3, which are likely exposed during binding to the IR, and LeuA13, ValB12, and LeuB17 that maintain secondary structure.…”

“…endocrinology ͉ insect ͉ reproduction ͉ vector V ertebrates and invertebrates produce a diversity of insulin-like peptide (ILP) superfamily members distinguished by a shared structural motif (1)(2)(3). Most ILPs are expressed as prepropeptides that consist of four major domains (Pre, B, C, and A).…”

Biophysical Optimization of a Therapeutic Protein by Nonstandard Mutagenesis

“…1A) (1). Although the hormone functions as a Zn 2ϩ -free monomer in the bloodstream (2), it is stored in pancreatic ␤-cells as a Zn 2ϩ -stabilized hexamer (3). Such self-assembly is of overarching importance to stable pharmaceutical formulation.…”

Structural Determinants of the Insulin Receptor-related Receptor Activation by Alkali

“…Generally, receptor tyrosine kinases are activated due to ligand-induced dimerization followed by autophosphorylation of intracellular catalytic domains (9,10). In the case of the insulin receptor minifamily, the receptor monomers are predimerized by disulfide bonds, and ligand binding induces a major conformational change that eventually results in the catalytic subunits approaching each other (11,12 disulfide-linked hydrophilic extracellular ␣-subunit and membrane-bound ␤-subunit with a phosphotyrosine kinase domain (13).…”