Cells explore their environment by sensing and responding to mechanical forces. Many fundamental cellular processes, such as cell migration, differentiation, and homeostasis, take advantage of this sensing mechanism. At molecular level mechanosensing is mainly driven by mechanically active proteins. These proteins are able to sense and respond to forces by, e.g., undergoing conformational changes, exposing cryptic binding sites, or even by becoming more tightly bound to one another. In humans, defective responses to forces are known to cause a plethora of pathological conditions, including cardiac failure, pulmonary injury and are also linked to cancer. Microorganisms also take advantage of mechano-active proteins and proteins complexes. Employing single-molecule force spectroscopy with an atomic force microscope (AFM) and steered molecular dynamics (SMD) simulations we have investigated force propagation pathways through a mechanically active protein complexes.

Spotlight: Cells Sense Push and Pull (Mar 2002)

Stretching Fibronectin Modules

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Cells in animals adhere to dynamic, seemingly random assemblies with other cells that make up tissues like skin, organs, and brain. The cell's adhesion and motion is controlled by the extracellular matrix, with the protein fibronectin being a key component. The proteins have optimal mechanical elasticity and also signal to cell surface receptors, integrins, the tension exerted on them. How this is achieved is the subject of an ongoing collaboration with the research group of Viola Vogel of the Department of Bioengineering at the U. of Washington in Seattle (see also Oct 2001 highlight). The most recent publication from this effort reports a 97,884 atom steered molecular dynamics simulation using NAMD. It is revealed now that stretching two consecutive domains of fibronectin deforms two sites, the so-called RGD and synergy sites as well as their distance. This weakens binding to cell receptors and, as a result, integrins can function as gauges that signal the magnitude of exterior forces to a cell.

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  • Ultrastable cellulosome-adhesion complex tightens under load. Constantin Schoeler, Klara H. Malinowska, Rafael C. Bernardi, Lukas F. Milles, Markus A. Jobst, Ellis Durner, Wolfgang Ott, Daniel B. Fried, Edward A. Bayer, Klaus Schulten, Hermann E. Gaub, and Michael A. Nash. Nature Communications, 5:5635, 2014.
  • Mapping mechanical force propagation through biomolecular complexes. Constantin Schoeler, Rafael C. Bernardi, Klara H. Malinowska, Ellis Durner, Wolfgang Ott, Edward A. Bayer, Klaus Schulten, Michael A. Nash, and Hermann E. Gaub. Nano Letters, 15:7370-7376, 2015.
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    General Medical Sciences
    of the National Institutes
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