Mechanochemical switches in Angiostatin: a novel coupling between protein mechanochemistry and redox regulation.

A novel mechanism is proposed by which the triggering of a biochemical signal can be controlled by the hierarchical coupling between a protein redox equilibrium and an external mechanical force. We have characterized this mechanism in angiostatin, where the access to partially unfolded structures is controlled by mechanochemical switches. We provide evidence that these structures can act as the antiangiogenic active forms of this protein, rather than the native fully oxidized and folded one as commonly considered so far.We have identified a metastable intermediate that is specifically accessible in the thioredoxin-rich reducing conditions like those met by angiostatin on the surface of a tumor cell. The structure of the same intermediate accounts for unexplained data on the antiangiogenic activity of angiostatin. The mechanochemical paradigm herein proposed constitutes, to our knowledge, the first example of the coupling of a redox and a mechanical regulation and has broad implications for redox biology. It applies in particular to the large set of proteins that are composed by independent modules containing internal disulfide bonds and experience environmental mechanical stresses in-vivo.