Detection of an Integrin-Binding Mechanoswitch within Fibronectin during Tissue Formation and Fibrosis

5 years ago

Detection of an Integrin-Binding Mechanoswitch within Fibronectin during Tissue Formation and Fibrosis

John Nicosia, Haylee Bachman, Lars Holmgren, Ashley C. Brown, Yuanyuan Zhang, Lizhi Cao, Jacqueline Larouche, Thomas H. Barker

Fibronectin (Fn) is an extracellular matrix protein that orchestrates complex cell adhesion and signaling through cell surface integrin receptors during tissue development, remodeling, and disease, such as fibrosis. Fn is sensitive to mechanical forces in its tandem type III repeats, resulting in extensive molecular enlongation. As such, it has long been hypothesized that cell- and tissue-derived forces may activate an “integrin switch” within the critical integrin-binding ninth and 10th type III repeats—conferring differential integrin-binding specificity, leading to differential cell responses. Yet, no direct evidence exists to prove the hypothesis nor demonstrate the physiological existence of the switch. We report direct experimental evidence for the Fn integrin switch both in vitro and ex vivo using a scFv engineered to detect the transient, force-induced conformational change, representing an opportunity for detection and targeting of early molecular signatures of cell contractile forces in tissue repair and disease.

Publisher URL: http://dx.doi.org/10.1021/acsnano.7b02755

DOI: 10.1021/acsnano.7b02755