Structural Determinants of the Mechanical Stability of α-Catenin

Abstract

Background:We investigated how ␣-catenin transduces force at cell-to-cell adhesions. Results: Molecular dynamics simulations identified structural features contributing to ␣-catenin stability and its deformation under applied force. Conclusion: A cooperative network of salt bridges in ␣-catenin regulates both ␣-catenin stability and how it unfolds under force. Significance: These findings reveal the molecular basis of experimental observations and the impact of reported cancer-linked ␣-catenin mutants.

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

“…If each salt bridge roughly contributes 4 − 8 k B T to the overall barrier [49], this is consistent with the magnitude of H. Molecular dynamics simulations also point to the stabilizing role of the salt bridges. Li et al [32] compared trajectories measuring the M2-M3 angle for the wild-type structure, initially starting in the small α state, to trajectories of mutants where one of the salt bridges is disrupted (i.e. E521A or R551A).…”

“…The angle between the bundles (denoted by α in Fig. 1) is likely to alter under applied tension, and thus the rotation of M3 with respect to M2 is a natural candidate for the main force-sensitive conformational change [32,43]. For a catch bond to exist, conformations with small α should be associated with weaker FABD-actin binding, and those with larger α with stronger FABD-actin binding.…”

“…This rotation mechanism of catch-bond formation, where the relative orientation between two protein domains is coupled to the bond strength, has proven successful in explaining both experimentally and theoretically the catch bonds in several selectin systems [33,45], and has recently been suggested as the underlying mechanism in catch bonds between the Notch receptor and certain ligands [36]. One important complication for αE-catenin, not present in the selectin cases, is the existence of a significant energy barrier to rotation: crystal structures [41,43] and molecular dynamics simulations [32] highlight a number of salt bridges among the M-domains that stabilize the small-α orientation of M2 and M3. This will prove a crucial ingredient in explaining the dynamics and functional role of the bond, as we will discuss in more detail later.…”

“…There is no direct connection between the fitted parameters and the structural features of those states, no way of estimating energy barriers, and no ability to rationalize or predict the results of mutation experiments on the bond lifetimes. Atomistic molecular dynamics simulations give important structural insights [29][30][31][32], but have their own limitations: conformational transitions and bond breaking in adhesion complexes at physiological forces typically occur on timescales (ms -s) many orders of magnitude larger than those accessible by allatom simulations, precluding direct comparison to force spectroscopy experiments. Thus a compromise is needed, an approach that is able to fit experimental data, but with results that also have a concrete structural interpretation.…”

Regulation of α-catenin conformation at cadherin adhesions

“…The idea that α-catenin samples multiple conformations during a force cycle in the cellular context as alluded above (Fig. 2) is reinforced by the observation that the intramolecular interactions (Li et al, 2015) in the auto-inhibited 'closed' conformation of α-catenin are not as strong as seen in other mechanically regulated adaptor proteins. For instance, the vinculin head domain can bind to the vinculin binding site in α-catenin in solution suggesting that the biochemical interaction between α-catenin and vinculin head domain could overcome the interdomain interactions in α-catenin in the absence of any physical force (Choi et al, 2012;Ishiyama et al, 2013).…”