Structural Conservation of Insulin/IGF Signalling Axis at the Insulin Receptors Level in Drosophila and Humans

Abstract The family of insulin-related hormones regulates key life processes in Metazoa, from metabolism to growth, reproduction, lifespan and aging, through an evolutionarily conserved Insulin/insulin-like growth factor-1 (IGF-1) signalling (IIS) axis. In humans the IIS axis is controlled by insulin, two insulin-like growth factors, two isoforms of the insulin receptor (hIR-A and -B), its homologous IGF-1R and their hybrid dimers. In Drosophila, this signalling engages seven insulin-like proteins (DILP1-7) and a single receptor (dmIR), with many downstream proteins and pathways that are homologous with human ones. This report reveals the first cryoEM structure of the dmIR ectodomain:DILP5 complex providing the evidence of structural homology between dmIR and hIR. In the presence of excess hormone, the overall organisation of the dmIR complex is an asymmetric ‘T’ conformation, similar to that observed in some human IR structures. However, dmIR binds three DILP5 molecules in an unseen arrangement, revealing unique structural signatures that could rationalize the selective binding and signalling by different DILPs. This work provides structural proof of the evolutionary conservation of key receptors of the insulin-like hormones signalling axis, underpinning a deeper understanding of an important model animal organism.