Dynamic structure of plasma fibronectin

Abstract

Fibronectin is a large vertebrate glycoprotein that is found in soluble and insoluble forms and involved in diverse processes. Protomeric fibronectin is a dimer of subunits, each of which comprises 29 to 31 modules—12 type I, two type II, and 15-17 type III. Plasma fibronectin is secreted by hepatocytes and circulates in a compact conformation before it binds to cell surfaces, converts to an extended conformation, and is assembled into fibronectin fibrils. Here we review biophysical and structural studies that have shed light on how plasma fibronectin transitions from the compact to the extended conformation. The three types of modules each have a well-organized secondary and tertiary structure as defined by NMR and crystallography and have been likened to “beads on a string”. There are flexible sequences in the N-terminal tail, between the fifth and sixth type I modules, between the first two and last two of the type III modules, and at the C-terminus. Several specific module-module interactions have been identified that likely maintain the compact quaternary structure of circulating fibronectin. The quaternary structure is perturbed in response to binding events, including binding of fibronectin to the surface of vertebrate cells for fibril assembly and to bacterial adhesins.

Plasma fibronectin stabilizes Borrelia burgdorferi –endothelial interactions under vascular shear stress by a catch-bond mechanism

“…3H), indicating that even in the absence of BBK32-dependent pFn polymerization and interaction stabilization by catch bonds, pFn promotes B. burgdorferi-endothelial interactions under shear stress. This increase in interactions could be because pFn recruitment expands the range of endothelial cell surface molecules (e.g., heparin-sulfated GAGs, integrins, nonintegrin receptors) with which bacteria can interact (11,21). It is also possible that force-driven Fn polymerization (42) promotes binding of pFn on bacterial surfaces to insoluble Fn deposited on endothelial surfaces.…”

“…Bacterial exploitation of pFn to facilitate endothelial interactions under flow may increase the risk of pathological infection outcomes such as endocarditis, colonization of cardiac and other devices, bacterial dissemination to secondary infection sites, and possibly immune evasion secondary to invasion of endothelial cells themselves (12,20,22). BBK32 binds to the N-terminal fibrillogenesis region of Fn by the same tandem β-zipper mechanism exhibited by FnBPs from genetically distant staphylococcal and streptococcal bacteria, suggesting the possibility that FnBPs from other disseminating bacterial pathogens that also induce structural rearrangement of pFn (12,21) have the potential to strengthen and stabilize bacterial-vascular interactions by a catch-bond mechanism. For one of these adhesins, S. aureus FnBPA, polymorphisms that increase the frequency and strength of Fn binding are associated with increased risk of infection of cardiac devices in patients (20,29).…”

“…This pFn is ordinarily a compact, nonadhesive dimer in which most ligand-binding sites are buried. Preservation of the inert, nonadhesive properties of this molecule is important in blood, where constitutive exposure of pFn ligand-binding sites would affect blood flow, thrombosis, and movement and adhesion of circulating cells (11,21). However, upon activation or force-induced stretching or conformational change induced by certain FnBPs, pFn undergoes a conformational change that exposes ligand-binding sites (11,12,26,27,35).…”

“…Most invasive bacterial pathogens that infect vertebrates target Fn and can adhere to this highly conserved molecule via bacterial cell surface adhesion proteins (adhesins) collectively referred to as bacterial Fn-binding proteins (FnBPs) (12,21,22). FnBPs can adhere to the insoluble Fn matrix and soluble unpolymerized Fn produced by most host cells, and many FnBPs also bind pFn, which is produced by the liver and is important for hemostasis and wound healing in vertebrates (23,24).…”

“…BBK32, which binds to Fn by a mechanism similar to the binding mechanisms of S. aureus FnBPA and streptococcal FnBPs (21,25), causes conformational changes in pFn that induce formation of an extended structure (26) and formation of superfibronectin, a highly cross-linked, exceptionally sticky, polymerized form of Fn (27,28). Several other pathogens and FnBPs adhere to Fn under force conditions similar to the force conditions found in the vasculature, suggesting that the use of Fn for vascular adhesion may be widespread among microbes (29)(30)(31)(32).…”