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Curr Biol. 2011 Dec 20;21(24):2046-54. doi: 10.1016/j.cub.2011.11.037. Epub 2011 Dec 8.

The single-molecule mechanics of the latent TGF-β1 complex.

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  • 1Laboratory of Cell Biophysics, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.

Abstract

BACKGROUND:

TGF-β1 controls many pathophysiological processes including tissue homeostasis, fibrosis, and cancer progression. Together with its latency-associated peptide (LAP), TGF-β1 binds to the latent TGF-β1-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-β1 from ECM stores. Latent TGF-β1 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-β1 release. We demonstrate the unfolding of two LAP key domains for mechanical TGF-β1 activation: the α1 helix and the latency lasso, which together have been referred to as the "straitjacket" that keeps TGF-β1 associated with LAP. The simultaneous unfolding of both domains, leading to full opening of the straitjacket at a force of ~40 pN, was achieved only when TGF-β1 was bound to the LTBP-1 in the ECM.

CONCLUSIONS:

Our results directly demonstrate opening of the TGF-β1 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-β1 to LTBP-1 is mandatory. Interfering with mechanical activation of latent TGF-β1 by reducing integrin affinity, cell contractility, and binding of latent TGF-β1 to the ECM provides new possibilities to therapeutically modulate TGF-β1 actions.

Copyright © 2011 Elsevier Ltd. All rights reserved.

PMID:
22169532
[PubMed - indexed for MEDLINE]
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