Abstract
Life is an emergent property of transient interactions between biomolecules and other organic and inorganic molecules that somehow leads to harmony and order. Measurement and quantitation of these biological interactions are of value to scientists and are major goals of biochemistry, as affinities provide insight into biological processes. In an organism, these interactions occur in the context of forces and the need for a consideration of binding affinities in the context of a changing mechanical landscape necessitates a new way to consider the biochemistry of protein–protein interactions. In the past few decades, the field of mechanobiology has exploded, as both the appreciation of, and the technical advances required to facilitate the study of, how forces impact biological processes have become evident. The aim of this review is to introduce the concept of force dependence of biomolecular interactions and the requirement to be able to measure force-dependent binding constants. The focus of this discussion will be on the mechanotransduction that occurs at the integrin-mediated adhesions with the extracellular matrix and the major mechanosensors talin and vinculin. However, the approaches that the cell uses to sense and respond to forces can be applied to other systems, and this therefore provides a general discussion of the force dependence of biomolecule interactions.
Highlights
Life is an emergent property of transient interactions between biomolecules and other organic and inorganic molecules that somehow leads to harmony and order
The purpose of this review is to provide a brief introduction to the concept of force-dependent binding constants, and we will introduce the study of how forces can impact biomolecular interactions
The first section will be a general discussion of biomolecular interactions and their importance in biological processes; in particular, this section will focus on the protein interactions involved in mechanotransduction leading to the appreciation that many of these protein interactions have a force-dependent component
Summary
Force results in the loss of ligands binding to folded rod domains; eight of the 13 talin rod domains contain vinculin binding sites (VBSs), amphipathic helices in which the vinculin binding epitope is buried inside the domain. At low force, the affinity of the VBS interaction with vinculin is weak (it has a high Kd) as the binding site is not accessible to vinculin. The Kd profile with force is different, at low force, the Kd is high as binding is not possible, at forces above the unfolding threshold, the Kd is low [exposed VBS bind tightly to the vinculin head, with a nanomolar Kd ( as we will see the vinculin itself is regulated by forces acting on vinculin)]. The force dependence is complicated as at high forces the VBS helix can unfold and lead to a loss of vinculin binding
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