Differential Binding of GIGYF1 and GIGYF2 to GRB10 in Humans: Implications for Insulin and IGF-1 Signaling

Cognitive impairment associated with insulin and insulin-like growth factor 1 (IGF-1) resistance represents a significant and escalating public health concern, particularly in the context of the rising prevalence of Type 2 diabetes (T2D).This resistance is intricately linked to neurodegenerative and neurodevelopmental disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and autism spectrum disorder (ASD), all of which are projected to increase in incidence.Central to these conditions is the dysfunction of insulin receptor (ISR) and IGF-1 receptor (IGF-1R) signaling pathways in the brain, leading to disruptions in downstream cascades like PI3K/AKT and Ras/MAPK.These disruptions impair critical cellular functions, including glucose transport, due to the mislocalization of the GLUT4 transporter.In murine models, three key proteins-Growth factor receptor-bound protein 10 (GRB10), and GRB10interacting GYF proteins 1 and 2 (GIGYF1 and GIGYF2)-have been identified as negative regulators of ISR and IGF-1R signaling.GRB10 directly binds to phosphorylated tyrosine residues on these receptors, attenuating signal transduction.GIGYF1 and GIGYF2, initially discovered through yeast two-hybrid assays as GRB10 interactors, are known to inhibit translation initiation via 4EHP-dependent and -independent mechanisms.In mice, these proteins interact with GRB10 through a conserved PPGF motif, a feature not present in other species.Furthermore, GIGYF1 and GIGYF2 have been implicated in the endosomal retention of ISR and IGF-1R, preventing their recycling to the cell surface and thereby exacerbating insulin resistance.Notably, GIGYF1 has been associated with ASD, GIGYF2 with PD, and GRB10 with AD.This study aims to elucidate the conservation and functional relevance of the GRB10-GIGYF1/2 interaction in humans.Through a series of binding affinity and in vitro assays, we demonstrate that, unlike in mice, human GIGYF2 does not interact with GRB10, while GIGYF1 retains this Table of Contents