Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 100, Issue 25, Pages 14784-14789Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2334390100
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Funding
- NCRR NIH HHS [5P41RR05969, P41 RR005969] Funding Source: Medline
- NIBIB NIH HHS [R01EB00249] Funding Source: Medline
- NIGMS NIH HHS [T32 GM008268, 5T32GM08268, 1R01GM60946] Funding Source: Medline
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Fibronectin (FN) forms fibrillar networks coupling cells to the extracellular matrix. The formation of FN fibrils, fibrillogenesis, is a tightly regulated process involving the exposure of cryptic binding sites in individual FN type III (FN-III) repeats presumably exposed by mechanical tension. The FN-III1 module has been previously proposed to contain such cryptic sites that promote the assembly of extracellular matrix FN fibrils. We have combined NMR and steered molecular dynamics simulations to study the structure and mechanical unfolding pathway of FN-III1. This study finds that FN-III1 consists of a beta-sandwich structure that unfolds to a mechanically stable intermediate about four times the length of the native folded state. Considering previous experimental findings, our studies provide a structural model by which mechanical stretching of FN-III1 may induce fibrillogenesis through this partially unfolded intermediate.
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