Structural basis of Drosophila insulin receptor activation by DILP2 hormone

Insulin related hormones regulate key life processes in the animal kingdom, from metabolism to growth, lifespan and aging, through an evolutionarily conserved insulin and insulin-like hormones signalling axis (IIS). In humans the IIS axis is controlled by insulin, two Insulin like Growth Factors, two isoforms of the insulin receptor (hIRA and hIRB), and its homologous IGF1R. In Drosophila, this signalling engages seven insulin-like hormones (DILP1 to 7) and a single receptor (dmIR) that follows the blueprint of hIR/hIGF1R. This report describes two cryoEM structures of the dmIR ectodomain dmIRECD:DILP2 complex, revealing their structural homology with dmIR:DILP5 complex. The high excess of DILP2 yielded two dmIRECD complexes in asymmetric conformations, similar to that observed in some complexes of hIR and in the dmIR-ECD:DILP5 complex. This stoichiometric and structural heterogeneity, yielding one- and two-DILP2:receptor complexes were not observed in DILP5:dmIR-ECD assembly. Also, the resistance of dmIR-ECD to form more DILP2 saturated complexes, despite very high excess of this hormone, suggest that the specificities of DILPs may lie in their kon/koff kinetic parameters. This work expands understanding of the dmIR conformational flexibility, suggesting also that insect dmIR follows more hIR rather than hIGF1R receptor signal transduction pattern induced by various DILPs.