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Forced Unfolding of the Fibronectin Type III Module Reveals a Tensile Molecular Recognition Switch

Andre Krammer, Hui Lu, Barry Isralewitz, Klaus Schulten and Viola Vogel
Proceedings of the National Academy of Sciences of the United States of America
Vol. 96, No. 4 (Feb. 16, 1999), pp. 1351-1356
Stable URL: http://www.jstor.org/stable/47205
Page Count: 6
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Forced Unfolding of the Fibronectin Type III Module Reveals a Tensile Molecular Recognition Switch
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Abstract

The 10th type III module of fibronectin possesses a β -sandwich structure consisting of seven β -strands (A-G) that are arranged in two antiparallel sheets. It mediates cell adhesion to surfaces via its integrin binding motif, Arg78, Gly79, and Asp80 (RGD), which is placed at the apex of the loop connecting β -strands F and G. Steered molecular dynamics simulations in which tension is applied to the protein's terminal ends reveal that the β -strand G is the first to break away from the module on forced unfolding whereas the remaining fold maintains its structural integrity. The separation of strand G from the remaining fold results in a gradual shortening of the distance between the apex of the RGD-containing loop and the module surface, which potentially reduces the loop's accessibility to surface-bound integrins. The shortening is followed by a straightening of the RGD-loop from a tight β -turn into a linear conformation, which suggests a further decrease of affinity and selectivity to integrins. The RGD-loop therefore is located strategically to undergo strong conformational changes in the early stretching stages of the module and thus constitutes a mechanosensitive control of ligand recognition.

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