Title : How
insulin engages its primary binding
site on the
insulin receptor
Abstract :
- Insulin receptor signalling has a central role in mammalian biology, regulating cellular metabolism, growth, division, differentiation and survival
- Insulin resistance contributes to the pathogenesis of type 2 diabetes mellitus and the onset of Alzheimer's disease; aberrant signalling occurs in diverse cancers, exacerbated by cross-talk with the homologous type 1 insulin-like growth factor receptor ( IGF1R )
- Despite more than three decades of investigation, the three-dimensional structure of the insulin- insulin receptor complex has proved elusive, confounded by the complexity of producing the receptor protein
- Here we present the first view, to our knowledge, of the interaction of insulin with its primary binding site on the insulin receptor , on the basis of four crystal structures of insulin bound to truncated insulin receptor constructs
- The direct interaction of insulin with the first leucine-rich-repeat domain leucine-rich-repeat domain ( L1 ) of insulin receptor is seen to be sparse, the hormone instead engaging the insulin receptor carboxy-terminal α-chain (αCT) segment, which is itself remodelled on the face of L1 upon insulin binding
- Contact between insulin and L1 is restricted to insulin B-chain residues
- The αCT segment displaces the B-chain C-terminal β-strand away from the hormone core, revealing the mechanism of a long-proposed conformational switch in insulin upon receptor engagement
- This mode of hormone-receptor recognition is novel within the broader family of receptor tyrosine kinases
- We support these findings by photo-crosslinking data that place the suggested interactions into the context of the holo receptor and by isothermal titration calorimetry data that dissect the hormone- insulin receptor interface
- Together, our findings provide an explanation for a wealth of biochemical data from the insulin receptor and IGF1R systems relevant to the design of therapeutic insulin analogues