Structures of insect Imp-L2 suggest an alternative strategy for regulating the bioavailability of insulin-like hormones

Abstract

The insulin/insulin-like growth factor signalling axis is an evolutionary ancient and highly conserved hormonal system involved in the regulation of metabolism, growth and lifespan in animals. Human insulin is stored in the pancreas, while insulin-like growth factor-1 (IGF-1) is maintained in blood in complexes with IGF-binding proteins (IGFBP1–6). Insect insulin-like polypeptide binding proteins (IBPs) have been considered as IGFBP-like structural and functional homologues. Here, we report structures of the Drosophila IBP Imp-L2 in its free form and bound to Drosophila insulin-like peptide 5 and human IGF-1. Imp-L2 contains two immunoglobulin-like fold domains and its architecture is unrelated to human IGFBPs, suggesting a distinct strategy for bioavailability regulation of insulin-like hormones. Similar hormone binding modes may exist in other insect vectors, as the IBP sequences are highly conserved. Therefore, these findings may open research routes towards a rational interference of transmission of diseases such as malaria, dengue and yellow fevers.

Impact of Probiotic Combination in InR[E19]/TM2 Drosophila melanogaster on Longevity, Related Gene Expression, and Intestinal Microbiota: A Preliminary Study

“…This result differs from Susan Westfall’s findings, which showed that probiotics and synbiotics could downregulate dilp2 , enhance lean body mass, and extend longevity [ 4 ]. Several studies have also shown that increased expression of Imp-L2 could lead to phenotypic modulation, including increased stored lipids, decreased reproductive capacity, and extended lifespan [ 56 , 57 ]. These changes are in accordance with the downregulation of IIS.…”

Cross-Linking/Mass Spectrometry Uncovers Details of Insulin-Like Growth Factor Interaction With Insect Insulin Binding Protein Imp-L2

“…Although proteins related to the IGFBP-rPs were also identified in Crustacea and reported to bind an ILP responsible for sexual differentiation (6), proteins corresponding to the “true” vertebrate IGFBP 1–6 were not identified in invertebrates. Instead, it seems that the function of IGFBPs is fulfilled by IBPs which are composed of two immunoglobulin-like (Ig) domains and bind ILPs (including human insulin and IGF-1) with nanomolar affinities (7). Recently, we solved the apo and holo crystal structures of 242 amino acid Drosophila imaginal morphogenesis protein-late 2 protein (Imp-L2) which is one of the insect IBPs (7).…”

“…Instead, it seems that the function of IGFBPs is fulfilled by IBPs which are composed of two immunoglobulin-like (Ig) domains and bind ILPs (including human insulin and IGF-1) with nanomolar affinities (7). Recently, we solved the apo and holo crystal structures of 242 amino acid Drosophila imaginal morphogenesis protein-late 2 protein (Imp-L2) which is one of the insect IBPs (7). We have shown that the ligand ( Drosophila ILP5 and human IGF-1) binding mode of Imp-L2 differs from that of IGFBPs.…”

“… (A) The crystal structure of Imp-L2:IGF-1 complex (PDB ID 6FF3). Imp-L2 Ig-NT and Ig-CT domains are in gray and green, respectively, and IGF-1 with its numbering is in magenta; A–G refer to the β-strand nomenclature as in Roed et al (7). Some parts of these proteins relevant to this work and unobserved in the crystal structure: 1–19 for the Imp-L1 and 22–42 for the IGF-1, are depicted as dashed lines (not up to a possible real scale); IGF-1 D-domain (63–70), also not visible in the complex and not present in the des(63-70)-IGF-1 analog is omitted for figure clarity.…”

“…However, despite all advances in structural biology, the insulin/insulin-like signaling axis contains plethora of very mobile, or disordered, protein interfaces that appear disordered and escape characterization. For example the end of the B-domain, the whole C-domain, and D-domain in IGF-1 were/are untraceable in the complexes of IGF-1 with its binding partners (7, 8).…”