Biology subjects

De Meyts, P.

Publications and source records attributed to De Meyts, P..

3 recordsLinked to original sources

bioRxiv2025

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 (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:DILP2 complex, revealing their structural homology with dmIR:DILP5 complex. The 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, 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 hIGF-1R receptor signal transduction pattern induced by various DILPs.

biochemistry↗

bioRxiv2025

Evolution of Insulin, Insulin-like Growth Factor, and Their Cognate Receptors in Vertebrates, Invertebrates, and Viruses

The insulin and insulin-like growth factor (IGF) system regulates essential biological functions such as growth, metabolism, and development. While its physiological roles are well characterized, the evolutionary origins and molecular diversification of its ligands and receptors remain incompletely defined. Here, we present the most comprehensive phylogenetic and sequence conservation analysis of this system to date, using over 1,000 sequences from vertebrates, invertebrates, and viruses. Our analyses reveal that insulin, IGF-1, and IGF-2 form distinct monophyletic clades that diverged after the emergence of vertebrates, with IGF-1 being the most conserved ligand. We show that IGF1R-binding residues, especially in the A- and B- domains of IGF-1, are highly conserved across vertebrates, while insulins Site 2 residues, which overlap with its dimerization and hexamerization surface, are more variable--correlating with the loss of hexamer formation in hystricomorphs, reptiles, and jawless fish. Unexpectedly, we identify a 12-amino acid insert in the insulin receptor (IR) of turtles and tortoises, previously thought to be unique to mammalian IR-B isoform, suggesting an earlier evolutionary origin of isoform diversity. We also show that marsupials and monotremes retain ancestral receptor domain features shared with reptiles and birds, and that avian insulins, particularly A-chain residues, are unusually conserved. Viral insulin/IGF-like peptides (VILPs) fall into two distinct clades that resemble either IGFs or insulin. Together, these findings illuminate the evolutionary architecture of the insulin/IGF system, highlight unexpected lineage-specific adaptations, and provide a framework for understanding hormone-receptor function across biology and therapeutic design.

evolutionary biology↗

bioRxiv2023

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

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 hitherto-unseen arrangement, showing also dmIR-specific features. This work adds structural support to evolutionary conservation of the IIS axis at the IR level, underpinning also a better understanding of an important model organism.

biochemistry↗