Force is a signal that cells cannot ignore.
Bottom Line: Cells sense biochemical, electrical, and mechanical cues in their environment that affect their differentiation and behavior.The molecular details underlying how cells respond to force are only beginning to be understood.Here we review tools for probing force-sensitive proteins and highlight several examples in which forces are transmitted, routed, and sensed by proteins in cells.
Affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195-7290.Show MeSH
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Mentions: Table 1 shows that tools for direct observation of individual protein interactions must operate with nanometer precision and on the piconewton force scale. Biophysical tools capable of this precision can be grouped into two categories: those that actively control position and therefore apply force (Figure 1, A–C) and those that passively measure force (similar to a strain gauge; Figure 1, D–F). To apply force actively to a protein interaction of interest, the interaction is typically recapitulated in vitro with one protein tethered to a glass coverslip and its binding partner tethered to a polystyrene bead for laser trapping (Ashkin and Dziedzic, 1987; Neuman and Block, 2004; Matthews, 2009), to a magnetic bead for magnetic tweezers (Smith et al., 1992; Strick et al., 1996; Guttenberg et al., 2000), or to the tip of a submicrometer cantilever for atomic force microscopy (AFM; Binnig et al., 1986). Another method, not illustrated in Figure 1, called the biomembrane force probe, can also be used to apply forces to protein–protein interactions; however, most investigators have moved toward the laser trapping, AFM, or magnetic beads platforms (Evans et al, 1995; Gourier et al., 2008; Neuman and Nagy, 2008). Proteins are typically tethered using well-established conjugation chemistries (Hermanson, 2013; Kim and Herr, 2013), and in general tethering is not a major limitation. The physical principles underlying these instruments are outside the scope of this Perspective (see review by Neuman and Nagy, 2008). However, all of them share the ability to manipulate the position of a tethered protein or complex with nanometer precision while observing the deflection of a sensor element (i.e., bead or AFM tip) from its resting position. This deflection is usually proportional to the force applied on the protein–protein interaction with sub-piconewton sensitivity.
Affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195-7290.