Understanding the role of IQ motif-containing GTPase-activating protein 1 as a potential disruptor of the essential adhesion module at cell-cell junctions

Abstract

A key mechanism of stabilization of Cadherin-based cell-cell adhesions is through a mechanically modulated interaction to cortical actin filaments. This interaction is facilitated by a cytoplasmic adhesion module comprising of a complex of β-catenin and α-catenin. Recent evidence shows that under specific conditions the β-catenin/α-catenin complex gets disrupted because of mechanical disregulation of the junction maintenance machinery. The IQ motif-containing GTPase-activating protein 1 (IQGAP1) plays apparently a vital role as an internal regulator of the adhesion module, which competes for binding on β-catenin with α-catenin and is able to dissociate the latter from the adhesion complex. The underlying molecular mechanism is poorly understood with no clear evidence on what types of interactions are critical for a potential disruption. In this work, we combine steered-molecular-dynamics simulations and a multi-step protein–protein docking framework to dissect how mechanical detachment of α-catenin from the adhesion complex modulates the interactions between IQGAP1 and β-catenin. Our simulations show that as α-catenin detaches from β-catenin, IQGAP1 docks with progressively favorable scores. Interfacial analysis and subsequent mutagenesis studies, allow us to predict a molecular mechanism for an IQGAP1-driven disruption of the junctional adhesion module that centers on early onset of key favorable electrostatic interactions. Graphical Abstract Schematic representation of the force-dependent unbinding of α-catenin from the β-catenin/α-catenin complex, and step-wise docking of IQGAP1 to the deformed complex. Here the force of unbinding may come from high contractile forces on an actin filament attached to the complex. One possible source of the contractile force is strong and prolonged attachment to myosin motor proteins at high ATP concentrations.