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: Body's Glue (Dec 2003)

Structures of FN-III-1

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Movies of stretching FN-III-1:
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Tissues of the human body are composed of specialized cells held together by a connective fabric of proteins, that form the knots of a net glueing cells together. Upon stretching tissues, the knots unravel, rendering the net larger, but mysteriously also firmer. A protein called fibronectin-III-1 plays a particularly important role in the latter respect. Atomic force microscopy revealed that under mechanical tension fibronectin-III-1 stretches to ten times its initial length; but is does so in two steps, the first stretching step leading to net strengthening. It had been discovered earlier that other fibronectins found between cells are made of two sheets packed like a sandwich, but the structure of fibronectin-III-1 remained elusive. In an experimental-computational collaboration reported recently, the structure has now been resolved that at first sight looked similar to the sandwich structure of the other fibronectins, but on closer inspection showed a weak and a strong sheet. Simulations using NAMD revealed that stretching of the protein unravels readily the weak sheet, and only therafter the strong sheet. It turns out that the strong sheet of fibronectin-III-1 by itself, known as anastellin, inhibits tumor growth. Stretching of fibronectin-III-1, as it occurs naturally in tissue, unravels apparently half of the protein to render it extremely adhesive, strengthening a protein net that prevents metastasis of cancer cells and also assists wound healing (press release, more).

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  • 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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