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 underlying hypothesis is that force induces a rotational transition between two conformations of α-catenin, overcoming a significant energy barrier due to a network of salt bridges. This transition allosterically regulates the energies at the interface between α-catenin and F-actin. The model allows us to predict these energetic changes, as well as highlighting the importance of the salt bridge rotational barrier. By stabilizing one of the α-catenin 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.

β-catenin links cell seeding density to global gene expression during mouse embryonic stem cell differentiation

“…It is known that E-cadherin forms a complex with β-catenin at adherens junctions ( Adhikari et al., 2018 ). Indeed, immunocytochemistry of E-cadherin showed prominent membrane staining at HD, and this was reduced at LD ( Figure S3 C).…”

Is There a Need for a More Precise Description of Biomolecule Interactions to Understand Cell Function?

“…Instead, the off-rate of so-called catch-bonds is lowest (and the bond lifetime is accordingly highest) for a value of the pulling force that is often of order of a few tens of piconewtons [72,108]. While much effort was made to elucidate the mechanisms of the so-called catch-bond phenomenon with molecular dynamics [109,110] and/or theoretical studies [106,111,112], no phenomenological equation gained a wide acceptance to replace Equation (4). Note also that some geometrical parameters, such as the force direction, are not accounted for by Bell's equation [98,113].…”

Neuromechanobiology: An Expanding Field Driven by the Force of Greater Focus

“…How force impacts cadherin bond dissociation has been examined using optical tweezers (Figure 1), AFM (Figure 4D) and BFP (Figure 4B). [184][185][186][187][188][189] The rigid and stable ectodomain structure is believed to facilitate the transmission of mechanical force. [190,191] N-cadherin is necessary for long term potentiation and spine enlargement, but not required for long term depression or spine density/morphology, suggesting that cadherins can selectively mediate synapse plasticity via N-cadherin presence in postnatal, excitatory synapses.…”