Forced unfolding of the fibronectin type III module reveals a tensile molecular recognition switch

André Krammer, Hui Lu, Barry Isralewitz, Klaus Schulten, Viola Vogel

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1351-1356
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number4
DOIs
StatePublished - Feb 16 1999

ASJC Scopus subject areas

  • General

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