Structural basis of <i>Drosophila</i> insulin receptor activation by DILP2 hormone

Abstract Insulin-related hormones regulate key life processes in the animal kingdom, from metabolism to growth, lifespan and ageing, 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 (hIR-A and -B), and its homologous IGF-1R. In Drosophila, this signalling engages seven insulin-like hormones (DILP1-7) and a single receptor (dmIR) that follows the blueprint of hIR/hIGF-1R. This report describes two cryo-EM structures of the dmIR ectodomain (dmIR-ECD) in complex with DILP2, revealing their relationship to other known DILP5/2/1 complexes. A high excess of DILP2 yielded two dmIR-ECD 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 was not observed in DILP5:dmIR-ECD and DILP2 full-length dmIR assemblies. Also, in contrast to DILP5, the resistance of DILP2 to form more dmIR-ECD–saturated complexes, despite very high 40 : 1 excess of this hormone, suggests some structural bases for DILP1-7 specificities. This work expands understanding of the dmIR conformational flexibility, indicating that insect dmIR follows a more hIR:IGF-1R receptor hybrid mode of structural signal transduction pattern induced by various two-chains DILPs.