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Dynamic Bonds and Their Roles in Mechanosensing Available online at www.sciencedirect.com ScienceDirect Dynamic bonds and their roles in mechanosensing 1,2 3,7 4,5,6,7 Cheng Zhu , Yunfeng Chen and Lining Arnold Ju Mechanical forces are ubiquitous in a cell’s internal structure and mechanosensing, by which the information encoded in external environment. Mechanosensing is the process that the the force waveform exerted from outside or within the cell employs to sense its mechanical environment. In receptor- cell is transduced biochemically into biological signals [3]. mediated mechanosensing, cell surface receptors interact with At the molecular level, mechanosensing involves force- immobilized ligands to provide a specific way to receive modulated interactions of and conformational changes in extracellular force signals to targeted force-transmitting, force- proteins where dynamic bonds play crucial roles. transducing and force-supporting structures inside the cell. Conversely, forces generated endogenously by the cell can be Cell surface receptors mediate mechanosensing by receiv- transmitted via cytoplasmic protein–protein interactions and ing force-modulated signals that come through specific regulate cell surface receptor activities in an ‘inside–out’ manner. ligands, providing an opportunity for researchers to use Dynamic force spectroscopy analyzes these interactions on and dynamic force spectroscopy (DFS) to study cell mechan- inside cells to reveal various dynamic bonds. What is more, by osensing. To take this opportunity requires upgrading the integrating analysis of molecular interactions with that of cell DFS techniques that were used to mainly study force- signaling events involved in force-sensing and force-responding dependent ligand binding and conformational change of processes, one can investigate how dynamic bonds regulate the purified receptors to allow experiments on live cells and to reception, transmission and transduction of mechanical signals. enable concurrent examination of molecular dynamics and cellular response to biomechanical stimulations (Figure 1a) Addresses [4]. These technological advances include: (1) Combining 1 Coulter Department of Biomedical Engineering, Georgia Institute of DFS withsimultaneousimagingofintracellularsignalingto Technology, Atlanta, GA 30332, USA 2 directly correlate molecular processes with the triggered Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA cellular responses on a single cell [5,6,7 ,8,9,10 ,11 ,12]; 3 Department of Molecular Medicine, MERU-Roon Research Center on (2) Expanding the list of live-cell molecular processes for Vascular Biology, The Scripps Research Institute, La Jolla, CA 92037, analysis from receptor–ligand binding to include integrin USA 4 (un)bending [13,14], protein unfolding [11 ,15–17], School of Biomedical Engineering, The University of Sydney, uncoupling [18–20], cleavage [21–23], molecular stiffness Camperdown, NSW 2006, Australia 5 Charles Perkins Centre, The University of Sydney, Camperdown, NSW [14,24,25 ,26 ,27], changes in the receptor’s intracellular 2006, Australia interaction [7 ,25 ], affinity maturation [26 ], and binding 6 Heart Research Institute, The University of Sydney, Camperdown, reinforcement [27,28]; (3) dual DFS systems for analysis of NSW 2006, Australia dual receptor crosstalk by quantifying the spatiotemporal Corresponding author: Zhu, Cheng ([email protected]) requirementsandfunctional consequencesof the upstream 7 These authors contributed equally. and downstream signaling events [29]. Here we review recent findings enabled by DFS on cells. We will focus on Current Opinion in Chemical Biology 2019, 53:88–97 ‘outside–in’ (Figure 1b) and ‘inside–out’ (Figure 1c) sig- This review comes from a themed issue on Chemical biophysics naling processes as modulated by mechanical forces via formation of receptor–ligand dynamic bonds and their Edited by Yan Jie and Terence Strick relevance to cell mechanosensing. Various receptor–ligand dynamic bonds and https://doi.org/10.1016/j.cbpa.2019.08.005 their biological roles 1367-5931/ã 2019 Elsevier Ltd. All rights reserved. In DFS experiments, three types of tensile force wave- forms have been employed to examine force modula- tion on receptor–ligand dissociation: ramped force, clamped force, and cyclic force (Figure 2a,b), resulting in multiple bond types with different responses to force, collectively referred to as dynamic bonds. The Introduction simplest and most widely used DFS assay is pulling As the building blocks of life that live in a stressful the bond until rupture, corresponding to a ramping mechanical milieu, cells are subjected to a myriad of force waveform (Figure 2a). Analysis of rupture force forces, including tension, compression, fluid shear, and distributions measured using a range of ramping rates hydrostatic pressure. Mechanobiology studies how a cell (Figure 2c) usually results in slip bonds where the senses, processes, responds, and adapts to mechanical average bond lifetime decreases (multi-)exponentially cues [1–3]. A crucial element of cell mechanobiology is with force [30–36] (Figure 2e). Using force-clamp DFS Current Opinion in Chemical Biology 2019, 53:88–97 www.sciencedirect.com Dynamic bonds in mechanosensing Zhu, Chen and Ju 89 Figure 1 may be attributed to the different force application his- tories experienced by the bonds, which has been shown to (a) affect their dissociation rate [35,44–46] (Figure 2f,g). a b RBC Bead Agreeing with this concept, the integrin 5 1–fibronectin Cell [28] and actin–actin [47] interactions manifests a ‘cyclic mechanical reinforcement (CMR) behavior where ramp- ing the force to a high level or loading the bond cyclically before measuring bond lifetimes at a lower clamped force 90° (Figure 2b) substantially prolongs the lifetime (Figure 2h). How and why different applied force wave- forms can elicit distinct dynamic bond types have yet to (b) (c) be fully elucidated. It may be related to the force- dependent conformation/extension fluctuations of the receptor and/or ligand, which can affect the formation of catch or slip bonds [48–50]. More importantly, it may Extracellular Extracellular be connected to the observation that distinct signals can F be induced by different applied force waveforms (see Signaling below). LigandCurrent Opinion in Chemical Biology Using the same force-clamp assay, whether a receptor– Integrin ligand interaction behaves as catch or slip bond may still depend on other factors. It may depend on the ligand Talin species and on the receptor’s activation state, as in the case where resting a b forms a catch bond with fibrin- Signal IIb 3 Actin ogen but slip bond with fibronectin, which both become more pronounced catch bonds when aIIbb3 is activated F [26 ]. The same ligand may form different bond types Intracellular Intracellular with cell surface and purified receptors, as in the case where fibrinogen forms slip bond with purified soluble Current Opinion in Chemical Biology aIIbb3 (containing only the ectodomain) [51,52] but catch bond with platelet membrane aIIbb3 [26 ]. In addition, Applying dynamic force spectroscopy (DFS) to study mechanical force loading direction was also shown to affect the catch outside–in and inside–out signaling. bond formation in an intracellular protein–protein inter- (a) An example DFS setup: Biomembrane Force Probe. A red blood action: the vinculin–actin catch bond required force to cell (RBC) is pressurized by a micropipette with a glass bead glued to the apex to act as the force transducer. The bead is functionalized by apply toward the pointed (–) end of the actin filament, the ligand of interest. On the opposing side, a cell expressing the which resulted in a 10-times long bond lifetime compared receptor of interest is held by a second micropipette, and brought into with when force was applied toward the barbed (+) end repeated contact with the bead to measure various kinetic and [53 ]. This polarity, or dependency of a dynamic bond mechanical properties of the receptor as it interacts with the ligand under force. (b, c) Mechanical outside–in (b) and inside–out (c) property on the F-actin end, has also been observed in signaling exemplified using the integrin system. Binding of a ligand to the CMR of G-actin–F-actin interactions where CMR is the integrin headpiece under tension can trigger outside–in mechano- more effective at the pointed end compared to that at the signaling across the membrane to regulate intracellular processes. barbed end [47]. It is worth noting that such a polarity was Vice versa, intracellular force transmitted from the cytoskeleton can not observed in the catch bonds of G-actin–F-actin inter- allosterically regulate ligand binding via the extracellular region of the integrin, causing inside–out signaling. actions [54], indicating catch bonds and CMR are distinct kinetic bond types independent from each other. assay (Figure 2a) to measure bond survival probabilities DFS complements other biophysical techniques in over a range of forces (Figure 2d), however, often reporting cell adhesion and cell signaling induced by observed catch bonds for the same interactions mechanical stimulations. The tension force waveforms [35,37–42], where the average bond lifetime increases employed by DFS need to be carefully selected to best with force in a certain regime before they turn into slip approximate the mechanical environment that cells expe- bonds at high forces (Figure 2e). In addition, ideal rience in vivo. On the cellular level,
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