Unraveling the mechanism of the cadherin-catenin-actin catch bond

Abstract

The adherens junctions between epithelial cells involve a protein complex formed by E-cadherin, β-catenin, α-catenin and F-actin. The stability of this complex was a puzzle for many years, since in vitro studies could reconstitute various stable subsets of the individual proteins, but never the entirety. The missing ingredient turned out to be mechanical tension: a recent experiment that applied physiological forces to the complex with an optical tweezer dramatically increased its lifetime, a phenomenon known as catch bonding. However, in the absence of a crystal structure for the full complex, the microscopic details of the catch bond mechanism remain mysterious. Building on structural clues that point to α-catenin as the force transducer, we present a quantitative theoretical model for how the catch bond arises, fully accounting for the experimental lifetime distributions. The model allows us to predict the energetic changes induced by tension at the interface between α-catenin and F-actin. It also identifies a significant energy barrier due to a network of salt bridges between two conformational states of α-catenin. By stabilizing one of these states, this barrier could play a role in how the complex responds to additional in vivo binding partners like vinculin. Since significant conformational energy barriers are a common feature of other adhesion systems that exhibit catch bonds, our model can be adapted into a general theoretical framework for integrating structure and function in a variety of force-regulated protein complexes.

A Simple Mechanical Model for Synthetic Catch Bonds

“…A very similar biphasic mechanism is observed in P-selectin 33 and cadherin proteins. 34 Tensile force applied to the ligand increases the probability of a transition from the open to the closed conformation, which leads to a prolonged lifetime at intermediate levels of tensile force. In short, the key features of catch bond proteins can be summarized as:…”

Catch bonds in sickle cell disease: shear-enhanced adhesion of red blood cells to laminin

“…( 2) to more detailed, structure-based models of the various adhesion interactions that collectively contribute to sRBC-LN bond dynamics (along the lines of Refs. (47,48)). The variation in 𝜏( 𝑓 ) among the 25 patients in Fig.…”