Abstract:Mechano-sensation of cells is an important prerequisite for cellular function, e.g. in the context of cell migration, tissue organisation and morphogenesis. An important mechano-chemical-transducer is the actin cytoskeleton. In fact, previous studies have shown that actin cross-linkers, such as α-actinin-4, exhibit mechanosensitive properties in its binding dynamics to actin polymers. However, to date, a quantitative analysis of tension-dependent binding dynamics in live cells is lacking. Here, we present a ne… Show more
“…1f, blue data). The single-molecule data provide direct proof of earlier speculations that α-actinin-4 forms weak catch bonds whilst the K255E point mutant forms strong slip bonds 13,14,25,27–30 .…”
Section: α-Actinin-4 Forms a Weak Catch Bond While The K255e Mutant Forms A Strong Slip Bondsupporting
confidence: 75%
“…It was furthermore proposed that the cryptic actin binding site is constitutively exposed by the K255E point mutation, increasing the binding affinity of α-actinin-4 but also abrogating its catch bond behavior (Fig. 1a, b) 13,14,25,27–30 . To directly test this idea, we tethered single α-actinin-4 molecules to polystyrene beads via DNA handles, and probed their binding to fluorescently tagged actin filaments, which fully coated another set of beads (Fig.…”
Section: α-Actinin-4 Forms a Weak Catch Bond While The K255e Mutant Forms A Strong Slip Bondmentioning
Molecular catch bonds are ubiquitous in biology and well-studied in the context of leukocyte extravasion1, cellular mechanosensing2,3, and urinary tract infection4. Unlike normal (slip) bonds, catch bonds strengthen under tension. The current paradigm is that this remarkable ability enables cells to increase their adhesion in fast fluid flows1,4, and hence provides ‘strength-on-demand’. Recently, cytoskeletal crosslinkers have been discovered that also display catch bonding5–8. It has been suggested that they strengthen cells, following the strength-on-demand paradigm9,10. However, catch bonds tend to be weaker compared to regular (slip) bonds because they have cryptic binding sites that are often inactive11–13. Therefore, the role of catch bonding in the cytoskeleton remains unclear. Here we reconstitute cytoskeletal actin networks to show that catch bonds render them both stronger and more deformable than slip bonds, even though the bonds themselves are weaker. We develop a model to show that weak binding allows the catch bonds to mitigate crack initiation by moving from low- to high-tension areas in response to mechanical loading. By contrast, slip bonds remain trapped in stress-free areas. We therefore propose that the mechanism of catch bonding is typified by dissociation-on-demand rather than strength-on-demand. Dissociation-on-demand can explain how both cytolinkers5–8,10,14,15 and adhesins1,2,4,12,16–20 exploit continuous redistribution to combine mechanical strength with the adaptability required for movement and proliferation21. Our findings provide a mechanistic understanding of diseases where catch bonding is compromised11,12 such as kidney focal segmental glomerulosclerosis22,23, caused by the α-actinin-4 mutant studied here. Moreover, catch bonds provide a route towards creating life-like materials that combine strength with deformability24.
“…1f, blue data). The single-molecule data provide direct proof of earlier speculations that α-actinin-4 forms weak catch bonds whilst the K255E point mutant forms strong slip bonds 13,14,25,27–30 .…”
Section: α-Actinin-4 Forms a Weak Catch Bond While The K255e Mutant Forms A Strong Slip Bondsupporting
confidence: 75%
“…It was furthermore proposed that the cryptic actin binding site is constitutively exposed by the K255E point mutation, increasing the binding affinity of α-actinin-4 but also abrogating its catch bond behavior (Fig. 1a, b) 13,14,25,27–30 . To directly test this idea, we tethered single α-actinin-4 molecules to polystyrene beads via DNA handles, and probed their binding to fluorescently tagged actin filaments, which fully coated another set of beads (Fig.…”
Section: α-Actinin-4 Forms a Weak Catch Bond While The K255e Mutant Forms A Strong Slip Bondmentioning
Molecular catch bonds are ubiquitous in biology and well-studied in the context of leukocyte extravasion1, cellular mechanosensing2,3, and urinary tract infection4. Unlike normal (slip) bonds, catch bonds strengthen under tension. The current paradigm is that this remarkable ability enables cells to increase their adhesion in fast fluid flows1,4, and hence provides ‘strength-on-demand’. Recently, cytoskeletal crosslinkers have been discovered that also display catch bonding5–8. It has been suggested that they strengthen cells, following the strength-on-demand paradigm9,10. However, catch bonds tend to be weaker compared to regular (slip) bonds because they have cryptic binding sites that are often inactive11–13. Therefore, the role of catch bonding in the cytoskeleton remains unclear. Here we reconstitute cytoskeletal actin networks to show that catch bonds render them both stronger and more deformable than slip bonds, even though the bonds themselves are weaker. We develop a model to show that weak binding allows the catch bonds to mitigate crack initiation by moving from low- to high-tension areas in response to mechanical loading. By contrast, slip bonds remain trapped in stress-free areas. We therefore propose that the mechanism of catch bonding is typified by dissociation-on-demand rather than strength-on-demand. Dissociation-on-demand can explain how both cytolinkers5–8,10,14,15 and adhesins1,2,4,12,16–20 exploit continuous redistribution to combine mechanical strength with the adaptability required for movement and proliferation21. Our findings provide a mechanistic understanding of diseases where catch bonding is compromised11,12 such as kidney focal segmental glomerulosclerosis22,23, caused by the α-actinin-4 mutant studied here. Moreover, catch bonds provide a route towards creating life-like materials that combine strength with deformability24.
“…Mei et al showed that increased tension of actin filaments increased α-catenin binding ( Figure 1 B) [ 36 ]. Hosseini et al showed that increased tension increases binding of the actin cross-linker, α-actinin-4, to actin [ 37 ]. LIM domain proteins, including members of the zyxin, paxillin, and FHL families, accumulate on mechanically stimulated actin via their LIM domains; increased binding of FHL prevents nuclear localization ( Figure 1 C) [ 38 ].…”
Section: Role Of the Cytoskeleton In Mechanotransductionmentioning
Mechanical cues are crucial for survival, adaptation, and normal homeostasis in virtually every cell type. The transduction of mechanical messages into intracellular biochemical messages is termed mechanotransduction. While significant advances in biochemical signaling have been made in the last few decades, the role of mechanotransduction in physiological and pathological processes has been largely overlooked until recently. In this review, the role of interactions between the cytoskeleton and cell-cell/cell-matrix adhesions in transducing mechanical signals is discussed. In addition, mechanosensors that reside in the cell membrane and the transduction of mechanical signals to the nucleus are discussed. Finally, we describe two examples in which mechanotransduction plays a significant role in normal physiology and disease development. The first example is the role of mechanotransduction in the proliferation and metastasis of cancerous cells. In this system, the role of mechanotransduction in cellular processes, including proliferation, differentiation, and motility, is described. In the second example, the role of mechanotransduction in a mechanically active organ, the gastrointestinal tract, is described. In the gut, mechanotransduction contributes to normal physiology and the development of motility disorders.
“…Interestingly, intrinsic dissociation rates for α-actinin and filamin, which were estimated with theoretical model using overall rupture-force probability distributions, are 0.066 ± 0.028 and 0.087 ± 0.073 , respectively 30 . Furthermore, lifetime of the disease-causing mutant K255E of human α-actinin-4 was measured as (155.1 s) 31 . Figure 4 Characterization of invadopodia protrusion.…”
Invadopodia are dynamic actin-rich membrane protrusions that have been implicated in cancer cell invasion and metastasis. In addition, invasiveness of cancer cells is strongly correlated with invadopodia formation, which are observed during extravasation and colonization of metastatic cancer cells at secondary sites. However, quantitative understanding of the interaction of invadopodia with extracellular matrix (ECM) is lacking, and how invadopodia protrusion speed is associated with the frequency of protrusion-retraction cycles remains unknown. Here, we present a computational framework for the characterization of invadopodia protrusions which allows two way interactions between intracellular branched actin network and ECM fibers network. We have applied this approach to predicting the invasiveness of cancer cells by computationally knocking out actin-crosslinking molecules, such as α-actinin, filamin and fascin. The resulting simulations reveal distinct invadopodia dynamics with cycles of protrusion and retraction. Specifically, we found that (1) increasing accumulation of MT1-MMP at tips of invadopodia as the duration of protrusive phase is increased, and (2) the movement of nucleus toward the leading edge of the cell becomes unstable as duration of the retractile phase (or myosin turnover time) is longer than 1 min.
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