title: Structure and functional significance of mechanically unfolded fibronectin type III1 intermediates.
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.
authors.affiliation: Beckman Institute and Department of Physics, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Mu
authors.initials: M
authors.lastname: Gao
authors.forename: David
authors.initials: D
authors.lastname: Craig
authors.forename: Olivier
authors.initials: O
authors.lastname: Lequin
authors.forename: Iain D
authors.initials: ID
authors.lastname: Campbell
authors.forename: Viola
authors.initials: V
authors.lastname: Vogel
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulten
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018076:DNA, Complementary / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D018625:Microscopy, Atomic Force; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D012984:Software
chemical_list: D018076:DNA, Complementary; D005353:Fibronectins