Journal
CURRENT BIOLOGY
Volume 21, Issue 24, Pages 2046-2054Publisher
CELL PRESS
DOI: 10.1016/j.cub.2011.11.037
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Funding
- Swiss National Science Foundation [3100A0-113733/1]
- Heart and Stroke Foundation Ontario [NA7086]
- Canadian Institutes of Health Research [210820]
- European Union [237946]
- Generalitat de Catalunya
- Novartis Stiftung fur Biologisch-Medizinische Forschung
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Background: TGF-beta 1 controls many pathophysiological processes including tissue homeostasis, fibrosis, and cancer progression. Together with its latency-associated peptide (LAP), TGF-beta 1 binds to the latent TGF-beta 1-binding protein-1 (LTBP-1), which is part of the extracellular matrix (ECM). Transmission of cell force via integrins is one major mechanism to activate latent TGF-beta 1 from ECM stores. Latent TGF-beta 1 mechanical activation is more efficient with higher cell forces and ECM stiffening. However, little is known about the molecular events involved in this mechanical activation mechanism. Results: By using single-molecule force spectroscopy and magnetic microbeads, we analyzed how forces exerted on the LAP lead to conformational changes in the latent complex that can ultimately result in TGF-beta 1 release. We demonstrate the unfolding of two LAP key domains for mechanical TGF-beta 1 activation: the alpha 1 helix and the latency lasso, which together have been referred to as the straitjacket that keeps TGF-beta 1 associated with LAP. The simultaneous unfolding of both domains, leading to full opening of the straitjacket at a force of similar to 40 pN, was achieved only when TGF-beta 1 was bound to the LTBP-1 in the ECM. Conclusions: Our results directly demonstrate opening of the TGF-beta 1 straitjacket by application of mechanical force in the order of magnitude of what can be transmitted by single integrins. For this mechanism to be in place, binding of latent TGF-beta 1 to LTBP-1 is mandatory. Interfering with mechanical activation of latent TGF-beta 1 by reducing integrin affinity, cell contractility, and binding of latent TGF-beta 1 to the ECM provides new possibilities to therapeutically modulate TGF-beta 1 actions.
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