Cyclic Mechanical Reinforcement of Integrin–Ligand Interactions

Abstract

Summary Cells regulate adhesion in response to internally-generated and externally-applied forces. Integrins connect the extracellular matrix to the cytoskeleton and provide cells with mechanical anchorages and signaling platforms. Here we show that cyclic forces applied to a fibronectin–integrin α5β1 bond switch the bond from a short-lived state with 1-s lifetime to a long-lived state with 100-s lifetime. We term this phenomenon “cyclic mechanical reinforcement” as the bond strength remembers the history of force application, accumulates over repeated cycles, but does not require force to be sustained. Cyclic mechanical reinforcement strengthens the fibronectin–integrin α5β1 bond through the RGD binding site of the ligand with the synergy binding site greatly facilitating the process. A flexible integrin hybrid domain is also important for cyclic mechanical reinforcement. Our results reveal a mechanical regulation of receptor–ligand interactions and identify a molecular mechanism for cell adhesion strengthening by cyclic forces.

Emerging properties of adhesion complexes: what are they and what do they do?

“…Upon ligand binding, integrins such as a5b1 form catch bonds whose conversion to a high-affinity state is stabilised by force [56] and whose bond strength 'remembers' force from previous applications [57]. This characteristic facilitates efficient and sustained mechanotransmission.…”

Probing the Instability of a Cluster of Slip Bonds Upon Cyclic Loads With a Coupled Finite Element Analysis and Monte Carlo Method

“…Beyond this critical force, the bond behaves as a slip bond, with lifetime decreasing with force [21,22], Here we are interested whether FAs would manifest the similar behavior upon cyclic stretch if FAs are mainly comprised of a cluster of slip bonds instead. What's more, a recent study suggested that the bond formed between y.5/S\ integrin and its ligand would shortly switch to a single state upon several cycles of periodical loading [24], after which the bond lifetime versus force may follow the Bell's law [25] that is for a slip bond.…”

Measurement Systems for Cell Adhesive Forces

“…They also showed that talin 1 is critical to the strength of this slip bond, suggesting that talin 1 is responsible for initiating this molecular slip bond between closely packed FN-integrin complexes [24]. Kong et al used AFM and membrane force probes to demonstrate that cyclic application of 5-25 pN forces to FN-integrin a 5 b 1 bond significantly increases bond lifetime and identified a mechanism for cell adhesion strengthening by the application of cyclic forces [25]. Furthermore, they demonstrated with AFM that increasing applied force between 10 and 30 pN prolongs integrin a 5 b 1 -FN fragment bond lifetime, demonstrating catch bond behavior [26].…”