Structural conservation of insulin/IGF signalling axis at the insulin receptors level in Drosophila and humans

Abstract

The insulin-related hormones regulate key life processes in Metazoa, from metabolism to growth, lifespan and aging, through an evolutionarily conserved insulin 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). This report describes the cryoEM structure of the dmIR ectodomain:DILP5 complex, revealing high structural homology between dmIR and hIR. The excess of DILP5 yields dmIR complex in an asymmetric ‘T’ conformation, similar to that observed in some complexes of human IRs. However, dmIR binds three DILP5 molecules in a distinct arrangement, showing also dmIR-specific features. This work adds structural support to evolutionary conservation of the IIS axis at the IR level, and also underpins a better understanding of an important model organism.

Biochemical characterization of the Drosophila insulin receptor kinase and longevity‐associated mutants

“…The structural changes that induce trans‐autophosphorylation of H‐IR kinase domains originate with the binding of insulin, triggering a shift of the third fibronectin type III domains (FnIII‐3) toward each other as evidenced by cryo‐EM structures 57,58 . A recent cryo‐EM structure of the extracellular domain of D‐IR bound to Drosophila insulin‐like peptide 5 (DILP5) indicates similar overall arrangements of the FnIII‐3 domains as in insulin bound H‐IR 59 . D‐IR‐specific loops in the FnIII domains provide additional stability for the DILP5 interaction; these modifications in the D‐IR extracellular domain may stabilize the receptor–ligand complex during DILP activation, allowing for distal autophosphorylation of the C‐termini YxxM motifs.…”