Abstract

Insulin receptor (IR) signaling plays a critical role in the regulation of metabolism and growth in multicellular organisms. IRs are unique among receptor tyrosine kinases in that they exist exclusively as covalent (αβ)2 homodimers at the cell surface. Transmembrane signaling by the IR can therefore not be based on ligand-induced dimerization as such but must involve structural changes within the existing receptor dimer. In this study, using glycosylated full-length human IR reconstituted into lipid nanodiscs, we show by single-particle electron microscopy that insulin binding to the dimeric receptor converts its ectodomain from an inverted U-shaped conformation to a T-shaped conformation. This structural rearrangement of the ectodomain propagates to the transmembrane domains, which are well separated in the inactive conformation but come close together upon insulin binding, facilitating autophosphorylation of the cytoplasmic kinase domains.

Highlights

  • The insulin receptor (IR) is a receptor tyrosine kinase involved in regulating glucose, protein, and lipid metabolism and growth

  • Using glycosylated full-length human insulin receptor reconstituted into lipid nanodiscs, we show that insulin binding to the dimeric receptor converts its ectodomains from an inverted U-shaped to a T-shaped conformation

  • The mechanism how insulin binding to the extracellular domains (ECDs) is transmitted by the transmembrane domains (TMDs) across the membrane to the cytoplasmic tyrosine kinase domains (TKDs) is unknown [8]

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Summary

Introduction

The insulin receptor (IR) is a receptor tyrosine kinase involved in regulating glucose, protein, and lipid metabolism and growth. ABSTRACT Using glycosylated full-length human insulin receptor reconstituted into lipid nanodiscs, we show that insulin binding to the dimeric receptor converts its ectodomains from an inverted U-shaped to a T-shaped conformation. The receptor was reconstituted into nanodiscs with membrane scaffold proteins (MSPs) and a ternary lipid mixture (Fig. 1b, c).

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Conclusion

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