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The fimbrial usher protein is involved in biogenesis of the pilus in Gram-negative bacteria. The biogenesis of some fimbriae (or pili) requires a two-component assembly and transport system which is composed of a periplasmic chaperone and a pore-forming outer membrane protein which has been termed a molecular 'usher'; this is the chaperone-usher pathway.[2][3][4]
The usher protein has a molecular weight ranging from 86 to 100 kDa and is composed of a membrane-spanning 24-stranded beta barrel domain, reminiscent of porins, and of four periplasmic soluble domains: an N-terminal one of about 120 residues (NTD),[1] a 'middle' domain of about 80 residues[5] located as a soluble insertion within the beta barrel region of the sequence (plug domain) and two IG-like domains (each about 80 residues long) at the C-terminus (CTD1 and CTD2).[6] Although the degree of sequence similarity of these proteins is not very high they share a number of characteristics. One of these is the presence of two pairs of disulfide bond-forming cysteines, the first one located in the NTD and the second in CTD2. The best conserved region of the sequence corresponds to the plug domain.
A fimbrial usher protein is a large, integral outer membrane protein found in Gram-negative bacteria. It plays a crucial role in the biogenesis and assembly of fimbriae (also known as pili), which are hair-like, proteinaceous appendages on the bacterial surface [1, 2, 4]. Fimbriae are essential virulence factors for many bacterial pathogens, mediating their attachment to host cells and tissues, biofilm formation, and other functions necessary for colonization and infection [4].
Structure
Fimbrial usher proteins are among the largest β-barrel outer membrane proteins (OMPs) identified to date, with molecular weights ranging from 86 to 100 kDa [1, 3]. Their complex structure is typically composed of several domains:
Transmembrane β-barrel domain: This is the core of the usher, forming a pore through the outer membrane. It is usually composed of 24 antiparallel β-strands, similar to porins [3, 4].
Periplasmic N-terminal domain (NTD): An N-terminal segment of about 120 residues that extends into the periplasm. The NTD is involved in recruiting chaperone-subunit complexes [3, 4].
Periplasmic C-terminal domains (CTD1 and CTD2): Two C-terminal domains also located in the periplasm. These domains interact with chaperone-subunit complexes and facilitate their translocation across the pore [3].
Plug domain: A globular domain located as a soluble insertion within the β-barrel. This domain acts as a gate, preventing premature pilus assembly and controlling channel opening. It can be positioned inside the pore or on the periplasmic side of the membrane [3, 4].
Fimbrial ushers often function as dimers in the outer membrane, although typically only one of the usher protomers (monomers) is actively involved in secretion at any given time [3, 4].
Mechanism of Action (Chaperone-Usher Pathway)
The fimbrial usher protein is the central component of the chaperone-usher pathway, a conserved mechanism used by many Proteobacteria to assemble fimbrial and nonfimbrial filaments on the bacterial surface [2, 4]. This pathway involves a coordinated series of steps:
Periplasmic Transport: Fimbrial subunits are synthesized in the cytoplasm and then transported across the inner membrane into the periplasm via the Sec general secretory pathway [2].
Chaperone Binding and Folding: In the periplasm, fimbrial subunits (which have an immunoglobulin (Ig)-like fold but lack a final β-strand) interact with specific periplasmic chaperones (e.g., PapD for P pili, FimC for Type 1 fimbriae). These chaperones bind to the hydrophobic cleft of the subunits, preventing their aggregation and ensuring proper folding and stability by providing a donor β-strand [2, 3].
Targeting to the Usher: The chaperone-fimbrial subunit complexes are then specifically targeted to the fimbrial usher, which is an integral outer membrane protein [2, 4].
Subunit Translocation and Polymerization: The usher acts as a sophisticated assembly platform and translocase. It facilitates the release of the fimbrial subunits from their chaperones and catalyzes their ordered polymerization. This process occurs through a mechanism called donor strand exchange, where the N-terminal β-strand of an incoming subunit replaces the chaperone's donor β-strand in the hydrophobic cleft of the preceding subunit. This sequential addition of subunits leads to the linear growth of the fimbrial filament [2, 4].
Secretion and Assembly: The growing fimbrial filament is secreted through the usher's channel to the bacterial surface, with the most distal proteins being secreted first. The pilus can then coil into its helical form extracellularly [2, 4]. The plug domain within the usher plays a role in regulating channel opening, likely moving into the periplasm upon activation to allow subunit passage [4].
Role in Bacterial Adherence and Pathogenesis
Fimbrial usher proteins, by assembling fimbriae, are crucial for bacterial adherence to host cells and tissues, a critical initial step in many bacterial infections. These fimbriae often carry an adhesin protein at their tip (e.g., FimH for Type 1 fimbriae, PapG for P pili) that specifically binds to receptors on host surfaces [2, 4].
Beyond simple adherence, fimbriae assembled by ushers also contribute to:
Biofilm formation: Fimbriae facilitate bacterial aggregation and the formation of biofilms, which can enhance bacterial survival and persistence in a host or on surfaces [4].
Motility: Some fimbriae can influence bacterial motility [4].
DNA transfer: Certain types of fimbriae are involved in DNA transfer (e.g., conjugation) [4].
Immune evasion: Fimbriae can modulate the host immune response [4].
The precise regulation of fimbrial usher protein expression and activity is complex, involving both global and operon-specific regulatory mechanisms, allowing bacteria to adapt to different host environments and optimize their colonization strategies [4]. Due to their essential role in bacterial pathogenesis, fimbrial ushers are considered potential targets for the development of new anti-infective strategies.
[1] Wurpel, D. J., Beatson, S. A., Totsika, M., Petty, N. K., & Schembri, M. A. (2013). Chaperone-Usher Fimbriae of Escherichia coli. PLoS ONE, 8(1), e52835.
[2] Sauer, F. G., Pinkner, J. S., Waksman, G., & Hultgren, S. J. (2002). Chaperone-usher pathway: an assembly system for microbial adhesion. Current Opinion in Microbiology, 5(1), 74-80.
[3] Remaut, H., Tang, C., Henderson, N. S., Pinkner, J. S., Wang, T., Hultgren, S. J., ... & Li, H. (2008). Fiber formation across the bacterial outer membrane by the chaperone/usher pathway. Cell, 133(4), 640-652.
[4] Phan, G., Remaut, H., Wang, T., Allen, W. J., Pirker, K. F., Lebedev, A., ... & Waksman, G. (2011). Crystal structure of the FimD usher bound to its cognate FimC-FimH substrate. Nature, 474(7349), 49-53.
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