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Surface Proteins of

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.
  • Author: Timothy J. Foster1
  • Editors: Vincent A. Fischetti2, Richard P. Novick3, Joseph J. Ferretti4, Daniel A. Portnoy5, Miriam Braunstein6, Julian I. Rood7
    Affiliations: 1: Microbiology Department, Trinity College, Dublin, Ireland; 2: The Rockefeller University, New York, NY; 3: Skirball Institute for Molecular Medicine, NYU Medical Center, New York, NY; 4: Department of Microbiology & Immunology, University of Oklahoma Health Science Center, Oklahoma City, OK; 5: Department of Molecular and Cellular Microbiology, University of California, Berkeley, Berkeley, CA; 6: Department of Microbiology and Immunology, University of North Carolina-Chapel Hill, Chapel Hill, NC; 7: Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia
  • Source: microbiolspec July 2019 vol. 7 no. 4 doi:10.1128/microbiolspec.GPP3-0046-2018
  • Received 19 October 2018 Accepted 01 November 2018 Published 05 July 2019
  • Timothy J. Foster, [email protected]
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  • Abstract:

    The surface of is decorated with over 20 proteins that are covalently anchored to peptidoglycan by the action of sortase A. These cell wall-anchored (CWA) proteins can be classified into several structural and functional groups. The largest is the MSCRAMM family, which is characterized by tandemly repeated IgG-like folded domains that bind peptide ligands by the dock lock latch mechanism or the collagen triple helix by the collagen hug. Several CWA proteins comprise modules that have different functions, and some individual domains can bind different ligands, sometimes by different mechanisms. For example, the N-terminus of the fibronectin binding proteins comprises an MSCRAMM domain which binds several ligands, while the C-terminus is composed of tandem fibronectin binding repeats. Surface proteins promote adhesion to host cells and tissue, including components of the extracellular matrix, contribute to biofilm formation by stimulating attachment to the host or indwelling medical devices followed by cell-cell accumulation via homophilic interactions between proteins on neighboring cells, help bacteria evade host innate immune responses, participate in iron acquisition from host hemoglobin, and trigger invasion of bacteria into cells that are not normally phagocytic. The study of genetically manipulated strains using animal infection models has shown that many CWA proteins contribute to pathogenesis. Fragments of CWA proteins have the potential to be used in multicomponent vaccines to prevent infections.

  • Citation: Foster T. 2019. Surface Proteins of . Microbiol Spectrum 7(4):GPP3-0046-2018. doi:10.1128/microbiolspec.GPP3-0046-2018.


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The surface of is decorated with over 20 proteins that are covalently anchored to peptidoglycan by the action of sortase A. These cell wall-anchored (CWA) proteins can be classified into several structural and functional groups. The largest is the MSCRAMM family, which is characterized by tandemly repeated IgG-like folded domains that bind peptide ligands by the dock lock latch mechanism or the collagen triple helix by the collagen hug. Several CWA proteins comprise modules that have different functions, and some individual domains can bind different ligands, sometimes by different mechanisms. For example, the N-terminus of the fibronectin binding proteins comprises an MSCRAMM domain which binds several ligands, while the C-terminus is composed of tandem fibronectin binding repeats. Surface proteins promote adhesion to host cells and tissue, including components of the extracellular matrix, contribute to biofilm formation by stimulating attachment to the host or indwelling medical devices followed by cell-cell accumulation via homophilic interactions between proteins on neighboring cells, help bacteria evade host innate immune responses, participate in iron acquisition from host hemoglobin, and trigger invasion of bacteria into cells that are not normally phagocytic. The study of genetically manipulated strains using animal infection models has shown that many CWA proteins contribute to pathogenesis. Fragments of CWA proteins have the potential to be used in multicomponent vaccines to prevent infections.

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Image of FIGURE 1

CWA surface proteins classified based on structural motifs. The primary translation products of all CWA proteins contain a signal sequence (S) at the amino terminus and a wall-spanning region (W, Xc) and sorting signal (SS) at the carboxyl terminus. The CWA proteins that are depicted are those for which structural analysis has facilitated classification into five distinct groups. Microbial surface components recognizing adhesive matrix molecules (MSCRAMMs). The clumping factor (Clf)-serine aspartate repeat (Sdr) group comprises proteins that are closely related to ClfA. ClfA and ClfB have a similar domain organization, whereas SdrC, SdrD, and SdrE contain additional B repeats that are located between the A domain and the serine-aspartate SD repeat R region. The N-terminal A region contains three separately folded domains, called N1, N2, and N3. Structurally, N2 and N3 form IgG-like folds that bind ligands by the DLL mechanism. Fibronectin-binding protein A (FnBPA) and FnBPB have A domains that are structurally and functionally similar to the A domain of the Clf-Sdr group. Located in place of the serine-aspartate repeat region are tandemly repeated fibronectin-binding domains (11 in FnBPA, 10 in FnBPB). The A region of the collagen adhesin (Cna) protein is organized differently than other MSCRAMMs, with N1 and N2 comprising IgG-like folds that bind to ligands using the collagen hug mechanism. The A region is linked to the wall-spanning and anchorage domains by variable numbers of B repeats. Near iron transporter (NEAT) motif protein family. The iron-regulated surface determinant (Isd) proteins have one (for IsdA), two (for IsdB), or three (for IsdH) NEAT motifs that bind to hemoglobin or heme. The figure depicts IsdA, which has a C-terminal hydrophilic stretch that reduces cell surface hydrophobicity and contributes to resistance to bactericidal lipids and antimicrobial peptides. Three-helical bundle motif protein A. The five N-terminal tandemly linked triple-helical bundle domains (known as EABCD) that bind to IgG and other ligands are followed by the repeat-containing Xr region and the nonrepetitive Xc region. G5-E repeat family. The alternating repeats of the G5 and E domains of surface protein G (SasG) (and the accumulation-associated protein [Aap] from ) link the N-terminal A region to the wall-spanning and anchorage domains. If the A domain is removed, the G5-E region can promote cell aggregation. Legume-lectin, cadherin-like domain protein. The BR region of the serine rich adhesin of platelets (SraP) protein is flanked by serine-rich repeat domains. The BR region comprises three distinct structural domains: the legume lectin-like, the β-grasp fold (β-GF), and the cadherin-like (CHLD) domains.

Source: microbiolspec July 2019 vol. 7 no. 4 doi:10.1128/microbiolspec.GPP3-0046-2018
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Image of FIGURE 2

MSCRAMM binding to ligand by DLL. Ribbon diagram showing the structure of the N2 (green) and N3 (yellow) subdomains of SdrG in the apo form and in complex with a peptide from the β-chain (purple) of fibrinogen following ligand binding by the DLL mechanism. The C-terminal extension of N3 in the apo form undergoes a conformational change following ligand binding, resulting in an additional β-strand in a β-sheet in subdomain N2 forming the latch (red) and lock (blue). The letters refer to β-strands.

Source: microbiolspec July 2019 vol. 7 no. 4 doi:10.1128/microbiolspec.GPP3-0046-2018
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Image of FIGURE 3

Schematic diagrams of MSCRAMMs before and after ligand binding. The top figure depicts an MSCRAMM in the apo form with the N2 (green) and N3 (yellow) subdomains shown as semicircles and the unstructured N1 subdomain. Serine residues in the flexible stalk are glycosylated, which prevents degradation by cathepsin. The middle diagram shows the conformational change in an MSCRAMM with respect to the bacterial cell that occurs following ligand binding by DLL. The C-terminal γ-chain peptide of fibrinogen is depicted by the red dashed line, and the gamma globule domain is in contact with the second ligand binding site in ClfA subdomain N3. It is not known if other MSCRAMMs have two binding sites on their ligands. The bottom diagram indicates that binding to fibrinogen by FnBPs exposes the N3 subdomain to plasminogen, which binds the MSCRAMM more efficiently in the presence of fibrinogen.

Source: microbiolspec July 2019 vol. 7 no. 4 doi:10.1128/microbiolspec.GPP3-0046-2018
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Image of FIGURE 4

SdrE binding to complement factor H. The top figure shows SdrE in the apo form with the unstructured N1 subdomain and the N2 and N3 subdomains (yellow and green semicircles, respectively). The loop that occludes the ligand binding trench is shown in blue. The bottom figure shows the conformational changes that occur when complement factor H binds by closed DLL. Factor H (red) can then engage nearby C3b molecules (blue) and facilitate binding and activation of the protease factor I, which cleaves C3b.

Source: microbiolspec July 2019 vol. 7 no. 4 doi:10.1128/microbiolspec.GPP3-0046-2018
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Image of FIGURE 5

Collagen binding protein and the collagen hug. The upper part shows a schematic diagram of the Cna protein in the apo form on the left and following binding by the collagen hug to the collagen triple helix on the right. Below is a ribbon diagram of the Cna protein in complex with the collagen triple helix. The N1 subdomain (green) and N2 subdomain (yellow) are separated by a long unfolded region (blue) that forms the lock around collagen (purple). β-strand complementation by the red strand completes the hug.

Source: microbiolspec July 2019 vol. 7 no. 4 doi:10.1128/microbiolspec.GPP3-0046-2018
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Image of FIGURE 6

Complement protein C1q. C1q is a complex of six identical heterotrimers that form a bouquet-like structure. The globular domains (blue, green, and cyan ovals) make up the six IgG binding sites. Each heterotrimer forms an extended collagen-like triple-helix stalk which coalesces into a complex stem. C1r and C1s bind to the triple-helix region and are displaced when Cna binds. The figure was kindly provided by Nicole Thielens, CNRA-CFE-Université Joseph Fournier, Grenoble, France.

Source: microbiolspec July 2019 vol. 7 no. 4 doi:10.1128/microbiolspec.GPP3-0046-2018
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Image of FIGURE 7

Homophilic interactions and biofilm formation. The upper part shows a schematic diagram of the model for homophilic interactions between the A domains of the MSCRAMMs FnBPA, FnBPB, and SdrC, which promote cell-cell accumulation of staphylococcal cells (yellow spheres) during biofilm formation. See Fig. 2 and 3 for the key. The lower part shows the extended fibrillar region of SdrG and Aap (orange and blue strands), which form extended zinc-dependent zipper interactions predicted to form a twisted rope-like structure.

Source: microbiolspec July 2019 vol. 7 no. 4 doi:10.1128/microbiolspec.GPP3-0046-2018
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Image of FIGURE 8

G5-E domains of SasG and Aap. The G5 (red) and E (blue) domains each form two triple-stranded β-helices separated by a short collagen-like triple helix.

Source: microbiolspec July 2019 vol. 7 no. 4 doi:10.1128/microbiolspec.GPP3-0046-2018
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Image of FIGURE 9

Fibronectin binding by FnBPs. The figure shows how one fibronectin binding repeat of the unstructured fibronectin binding region of FnBP binds to N-terminal type I modules of fibronectin by the tandem β zipper mechanism. Potentially up to 10 such interactions can occur per molecule of FnBP. Intramolecular interactions between the N-terminal type I modules and C-terminal type III modules result in allosteric activation of the 10th type III module, exposing an RGD motif which engages an αβ integrin on the surface of a mammalian cell to promote invasion by endocytosis.

Source: microbiolspec July 2019 vol. 7 no. 4 doi:10.1128/microbiolspec.GPP3-0046-2018
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Properties of CSA surface proteins

Source: microbiolspec July 2019 vol. 7 no. 4 doi:10.1128/microbiolspec.GPP3-0046-2018
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CWA proteins as colonization and virulence factors studied using animal models

Source: microbiolspec July 2019 vol. 7 no. 4 doi:10.1128/microbiolspec.GPP3-0046-2018

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