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.

Fig 1. A schematic diagram showing hypothetical conformational changes of the cadherin-catenin-actin complex under force.

A) A cartoon of the complex. In the absence of a crystal structure of the entirety, the diagram is drawn from the following PDB structures of various components: 3Q2V (E-cadherin), 3L6X (p120 catenin), 1I7W (β-catenin), 4IGG (αE-catenin), 1M8Q (F-actin). The arrangement of the structures relative to one another is a guess for the purposes of illustration. The theoretical model described in the text is independent of the details of this arrangement. B) The M region of αE-catenin, showing a conformation with small angle α between the M2 and M3 domains, favored at lower forces. The interactions (red dashed lines) between the adjacent F-actin binding domain (FABD) and F-actin depend on the conformational state of αE-catenin. C) Same as B, but in the large angle conformation, favored at larger forces. This results in an enhancement of FABD-actin interactions, leading to catch bond behavior.

Fig 2. Energy landscape of the Hamiltonian U from Eqs (1) and (2) in terms of r and α = π − θ − ϕ at force F = 0, with the parameters given in Table 1 and described in the text.

Energy contour labels are in units of k_BT. The vertical dashed line corresponds to the transition angle α_c, the horizontal dashed line to the natural bond length r₀, and the top edge to the distance r₀ + d beyond which the bond ruptures. The energy barriers to rupture are smaller in the region α ≤ α_c on the left, relative to the region α > α_c on the right. Since applied force F > 0 tilts the landscape toward larger inter-domain angles α, the mean bond lifetime will initially increase with force.

Fig 3. Experimental mean bond lifetime τ(F) versus force F (symbols) from Ref. [11] compared to the theoretical model with best-fit parameters from Table 1 (curve).

Fig 4. Bond survival probability Σ_F(t) versus time t for four different forces F.

Theory results are shown as curves, and the corresponding experimental data [11] as symbols.

Fig 5. The salt bridge network in the hinge region between the M1, M2, and M3 domains of αE-catenin (PDB: 4IGG) [41].

Fig 6. The effects of mutating the angular barrier height H from the original value of 25 k_BT down to zero, in increments of 5 k_BT, leaving all other model parameters fixed at their Table 1 values: A) the mean bond lifetime τ(F); B) the mean lifetime τ_L(F) of remaining in the large angle conformational state, α > α_c, measured from the initial time of entry into the state; C) the survival probability Σ_F(t) at F = 7 pN.