Dataset Information

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, ?-catenin, ?-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 ?-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 ?-catenin, overcoming a significant energy barrier due to a network of salt bridges. This transition allosterically regulates the energies at the interface between ?-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 ?-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.

SUBMITTER: Adhikari S

PROVIDER: S-EPMC6114904 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Adhikari Shishir S Moran Jacob J Weddle Christopher C Hinczewski Michael M

PLoS computational biology 20180817 8

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 ph ...[more]

PMID: 30118477

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Project description:The bacterial fimbrial adhesin FimH is a remarkable and well-studied catch-bond protein found at the tip of E. coli type 1 pili, which allows pathogenic strains involved in urinary tract infections to bind high-mannose glycans exposed on human epithelia. The catch-bond behavior of FimH, where the strength of the interaction increases when a force is applied to separate the two partners, enables the bacteria to resist clearance when they are subjected to shear forces induced by urine flow. Two decades of experimental studies performed at the single-molecule level, as well as x-ray crystallography and modeling studies, have led to a consensus picture whereby force separates the binding domain from an inhibitor domain, effectively triggering an allosteric conformational change in the former. This force-induced allostery is thought to be responsible for an increased binding affinity at the core of the catch-bond mechanism. However, some important questions remain, the most challenging one being that the crystal structures corresponding to these two allosteric states show almost superimposable binding site geometries, which questions the molecular origin for the large difference in affinity. Using molecular dynamics with a combination of enhanced-sampling techniques, we demonstrate that the static picture provided by the crystal structures conceals a variety of binding site conformations that have a key impact on the apparent affinity. Crucially, the respective populations in each of these conformations are very different between the two allosteric states of the binding domain, which can then be related to experimental affinity measurements. We also evidence a previously unappreciated but important effect: in addition to the well-established role of the force as an allosteric regulator via domain separation, application of force tends to directly favor the high-affinity binding site conformations. We hypothesize that this additional "local" catch-bond effect could delay unbinding between the bacteria and the host cell before the "global" allosteric transition occurs, as well as stabilizing the complex even more once in the high-affinity allosteric state.

Dataset Information

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

Publications

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

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