Structural Investigation of the Alkaline pH-Dependent Activation of Insulin Receptor-Related Receptor

Abstract

The general metadata -- e.g., title, author, abstract, subject headings, etc. -- is publicly available, but access to the submitted files is restricted to UT Southwestern campus access and/or authorized UT Southwestern users.Insulin receptor family, a subset of receptor tyrosine kinases governing metabolic balance and growth. Among them, the insulin receptor-related receptor stands out for its activation mechanism, which responds to alkaline pH rather than ligand binding. However, the precise workings of this pH-induced IRR activation have remained elusive due to the lack of high-resolution structural data. Our breakthrough comes with the cryo-EM structures of human IRR in two key states: the inactive state at neutral pH and the active state at alkaline pH. Through mutation studies and cellular experiments, we've unveiled the mechanism: as pH rises, repulsion forces between IRR's pH-sensing motifs disrupt its auto-inhibition, initiating a scissor-like rotation between two units and forming a "T"-shaped active conformation. This activated IRR dimer relies on specific interactions to stabilize itself. Our findings offer an unprecedented insight into the pH-dependent activation of IRR, paving the way for a deeper understanding of this critical receptor's structure-function relationship