Structure and functional significance of mechanically unfolded fibronectin type III1 intermediates

Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):14784-9. doi: 10.1073/pnas.2334390100. Epub 2003 Dec 1.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • DNA, Complementary / metabolism
  • Extracellular Matrix / metabolism
  • Fibronectins / chemistry*
  • Humans
  • Magnetic Resonance Spectroscopy
  • Microscopy, Atomic Force
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Folding
  • Protein Structure, Secondary
  • Sequence Homology, Amino Acid
  • Software

Substances

  • DNA, Complementary
  • Fibronectins

Associated data

  • PDB/1OWW