Mechanism of transmembrane signaling: Insulin binding and the insulin receptor

Transmembrane signaling via receptor tyrosine kinases generally requires ol igomerization of receptor monomers, with the formation of ligand-induced di mers or higher multimers of the extracellular domains of the receptors. Suc h formations are expected to juxtapose the intracellular kinase domains at the correct distances and orientations for transphosphorylation. For recept ors of the insulin receptor family that are constitutively dimeric, or thos e that form noncovalent dimers without ligands, the mechanism must be more complex. For these, the conformation must be changed by the ligand from one that prevents activation to one that is permissive for kinase phosphorylat ion. How the insulin ligand accomplishes this action has remained a puzzle since the discovery of the insulin receptor over 2 decades ago, primarily b ecause membrane proteins in general have been refractory to structure deter mination by crystallography. However, high-resolution structural evidence o n individual separate subdomains of the insulin receptor and of analogous p roteins has been obtained. The recently solved quaternary structure of the complete dimeric insulin receptor in the presence of insulin has now served as the structural envelope into which such individual domains were fitted. The combined structure has provided answers on the details of insulin/rece ptor interactions in the binding site and on the mechanism of transmembrane signaling of this covalent dimer. The structure explains many observations on the behavior of the receptor, from greater or lesser binding of insulin and its variants, point and deletion mutants of the receptor, to antibody- binding patterns, and to the effects on basal and insulin-stimulated autoph osphorylation under mild reducing conditions.