Mechanical Properties of β-Catenin Revealed by Single-Molecule Experiments

Abstract

β-catenin is a central component of the adaptor complex that links cadherins to the actin cytoskeleton in adherens junctions and thus, it is a good candidate to sense and transmit mechanical forces to trigger specific changes inside the cell. To fully understand its molecular physiology, we must first investigate its mechanical role in mechanotransduction within the cadherin system. We have studied the mechanical response of β-catenin to stretching using single-molecule force spectroscopy and molecular dynamics. Unlike most proteins analyzed to date, which have a fixed mechanical unfolding pathway, the β-catenin armadillo repeat region (ARM) displays low mechanostability and multiple alternative unfolding pathways that seem to be modulated by its unstructured termini. These results are supported by steered molecular dynamics simulations, which also predict its mechanical stabilization and unfolding pathway restrictions when the contiguous α-helix of the C-terminal unstructured region is included. Furthermore, simulations of the ARM/E-cadherin cytosolic tail complex emulating the most probable stress geometry occurring in vivo show a mechanical stabilization of the interaction whose magnitude correlates with the length of the stretch of the cadherin cytosolic tail that is in contact with the ARM region.

Tissue mechanics and fibrosis

“…NF-κB, which is downstream of many critical soluble factor pathways in fibrosis [44, 45], is also downstream of some mechanical forces. Wnt/β-catenin [46, 47], interleukins, and (as discussed above) G protein-coupled receptors and ion channels are common to both mechanical and soluble signaling pathways [41, 42]. Integrins and their downstream effector FAK are part of the cellular mechanotransduction apparatus but they also transduce signals from soluble factors.…”

Mechanotransduction in the Endothelium: Role of Membrane Proteins and Reactive Oxygen Species in Sensing, Transduction, and Transmission of the Signal with Altered Blood Flow

“…Kinases, phosphatases, and other signaling molecules provide a link between the sensing of shear stress and the transduction of this information to a physiological response. Candidate-transducing molecules include mitogen-activating protein kinases (MAPKs) (ERK, p38MAPK, JNK) (82,84,101), tyrosine kinases (22,151), NOXs (79,114), transcription factors (NFjB, AP-1) (17,62,139), growth factors (PDGF) (7,115), chemoattractants (MCP-1), cytokines (162), NO synthase (NOS), ET-1, and ROS as described above (103,125). The shear stimulus (onset, cessation), shear profile (laminar, oscillatory), and shear magnitude may determine which of these transducers is expressed and participates in signaling.…”

The mechanotransduction machinery at work atadherensjunctions

“…Additional force-dependent conformational changes in the cadherin-catenin complex may complete this molecular mechanosensing machinery. β-Catenin single molecule force spectroscopy has been performed using AFM at a pulling rate of 400 nm/s, but failed to reveal near-equilibrium transitions at low force and only unfolding at forces > 50 pN were observed [90], although this does not rule-out a physiological mechanosensor role of this protein. Finally, the cadherin extracellular domain has been described as forming catch bonds during homophilic trans interactions with a typical transition critical force of ~ 30 pN [91], which is well above the ~ 5 pN transition of α-catenin intramolecular transitions.…”