Understanding the Cooperative Interaction between Myosin II and Actin Cross-Linkers Mediated by Actin Filaments during Mechanosensation

AbstractMyosin II is a central mechanoenzyme in a wide range of cellular morphogenic processes. Its cellular localization is dependent not only on signal transduction pathways, but also on mechanical stress. We suggest that this stress-dependent distribution is the result of both the force-dependent binding to actin filaments and cooperative interactions between bound myosin heads. By assuming that the binding of myosin heads induces and/or stabilizes local conformational changes in the actin filaments that enhances myosin II binding locally, we successfully simulate the cooperative binding of myosin to actin observed experimentally. In addition, we can interpret the cooperative interactions between myosin and actin cross-linking proteins observed in cellular mechanosensation, provided that a similar mechanism operates among different proteins. Finally, we present a model that couples cooperative interactions to the assembly dynamics of myosin bipolar thick filaments and that accounts for the transient behaviors of the myosin II accumulation during mechanosensation. This mechanism is likely to be general for a range of myosin II-dependent cellular mechanosensory processes

Mechanoaccumulative elements of the mammalian actin cytoskeleton

To change shape, divide, form junctions, and migrate, cells reorganize their cytoskeletons in response to changing mechanical environments [1-4]. Actin cytoskeletal elements, including myosin II motors and actin crosslinkers, structurally remodel and activate signaling pathways in response to imposed stresses [5-9]. Recent studies demonstrate the importance of force-dependent structural rearrangement of α-catenin in adherens junctions [10] and vinculin's molecular clutch mechanism in focal adhesions [11]. However, the complete landscape of cytoskeletal mechanoresponsive proteins and the mechanisms by which these elements sense and respond to force remain to be elucidated. To find mechanosensitive elements in mammalian cells, we examined protein relocalization in response to controlled external stresses applied to individual cells. Here, we show that non-muscle myosin II, α-actinin, and filamin accumulate to mechanically stressed regions in cells from diverse lineages. Using reaction-diffusion models for force-sensitive binding, we successfully predicted which mammalian α-actinin and filamin paralogs would be mechanoaccumulative. Furthermore, a Goldilocks zone must exist for each protein where the actin-binding affinity must be optimal for accumulation. In addition, we leveraged genetic mutants to gain a molecular understanding of the mechanisms of α-actinin and filamin catch-bonding behavior. Two distinct modes of mechanoaccumulation can be observed: a fast, diffusion-based accumulation and a slower, myosin II-dependent cortical flow phase that acts on proteins with specific binding lifetimes. Finally, we uncovered cell-type and cell-cycle-stage-specific control of the mechanosensation of myosin IIB, but not myosin IIA or IIC. Overall, these mechanoaccumulative mechanisms drive the cell's response to physical perturbation during proper tissue development and disease

The emerging principle of force-sharing among actin cytoskeletal proteins

The actin cytoskeletal proteins in the cortex are the major players that sense mechanical cues and activate downstream signaling pathways (such as cell differentiation, migration and tissue morphogenesis) , as well as physiological processes (such as blood flow regulation and lung respiration) . Additionally, the actin cytoskeleton is associated with many diseases in heart and lung and governs the migration of cancer cells in these organs . Great effort has been invested in understanding the significance of the actin cytoskeleton from molecular to cellular to tissue levels . Most of these studies were focused on cell-substrate interactions and associated signaling pathways. Among them, the formation of stress fibers and focal adhesions were popularly investigated

Evolution of Spatial Structure of Tourist Flows for a Domestic Destination: A Case Study of Zhangjiajie, China

Transportation facilitates the flow of tourists generating tourist flows, which produce flow effects on the spatial scale. By analyzing the evolution of tourist flows in Zhangjiajie by various modes of transportation over a long time series, the results show that the degree of development of the destination transportation network affects the dominance of the tourism node. Specifically, in the “train period”, Zhangjiajie, Changsha, Fenghuang, and Jishou core destinations become dominant with the “Matthew Effect”. In the “road period”, Jishou and Mengdonghe destinations decline, with the “Filtering Effect”. In the “high-speed railway period”, Zhangjiajie and Changsha are connected with more distant origins, and the “Diffusion Effect” occurs. It is worth noting that the development of high-speed rail has created a substitution effect for trains over long distances, and self-driving has created a substitution effect for trains over short and medium distances

Noncovalent Modulation of the Inverse Temperature Transition and Self-Assembly of Elastin‑<i>b</i>‑Collagen-like Peptide Bioconjugates

Stimuli-responsive nanostructures produced with peptide domains from the extracellular matrix offer great opportunities for imaging and drug delivery. Although the individual utility of elastin-like (poly)­peptides and collagen-like peptides in such applications has been demonstrated, the synergistic advantages of combining these motifs in short peptide conjugates have surprisingly not been reported. Here, we introduce the conjugation of a thermoresponsive elastin-like peptide (ELP) with a triple-helix-forming collagen-like peptide (CLP) to yield ELP–CLP conjugates that show a remarkable reduction in the inverse transition temperature of the ELP domain upon formation of the CLP triple helix. The lower transition temperature of the conjugate enables the facile formation of well-defined vesicles at physiological temperature and the unexpected resolubilization of the vesicles at <i>elevated</i> temperatures upon unfolding of the CLP domain. Given the demonstrated ability of CLPs to modify collagens, our results not only provide a simple and versatile avenue for controlling the inverse transition behavior of ELPs, but also suggest future opportunities for these thermoresponsive nanostructures in biologically relevant environments