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Sortases, Surface Proteins, and Their Roles in Disease and Vaccine Development

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  • Authors: Olaf Schneewind1, Dominique Missiakas2
  • Editors: Maria Sandkvist3, Eric Cascales4, Peter J. Christie5
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    Affiliations: 1: Department of Microbiology, University of Chicago, Chicago, IL 60637; 2: Department of Microbiology, University of Chicago, Chicago, IL 60637; 3: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan; 4: CNRS Aix-Marseille Université, Mediterranean Institute of Microbiology, Marseille, France; 5: Department of Microbiology and Molecular Genetics, McGovern Medical School, Houston, Texas
  • Source: microbiolspec February 2019 vol. 7 no. 1 doi:10.1128/microbiolspec.PSIB-0004-2018
  • Received 20 August 2018 Accepted 02 January 2019 Published 08 February 2019
  • Olaf Schneewind, [email protected]; Dominique Missiakas, [email protected]
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  • Abstract:

    Sortases cleave short peptide motif sequences at the C-terminal end of secreted surface protein precursors and either attach these polypeptides to the peptidoglycan of Gram-positive bacteria or promote their assembly into pilus structures that are also attached to peptidoglycan. Sortase A, the enzyme first identified in the human pathogen , binds LPXTG motif sorting signals, cleaves between threonine (T) and glycine (G) residues, and forms an acyl enzyme between its active-site cysteine thiol and the carboxyl group of threonine (T). Sortase A acyl enzyme is relieved by the nucleophilic attack of the cross bridge amino group within lipid II, thereby generating surface protein linked to peptidoglycan precursor. Such products are subsequently incorporated into the cell wall envelope by enzymes of the peptidoglycan synthesis pathway. Surface proteins linked to peptidoglycan may be released from the bacterial envelope to diffuse into host tissues and fulfill specific biological functions. sortase A is essential for host colonization and for the pathogenesis of invasive diseases. Staphylococcal sortase-anchored surface proteins fulfill key functions during the infectious process, and vaccine-induced antibodies targeting surface proteins may provide protection against . Alternatively, small-molecule inhibitors of sortase may be useful agents for the prevention of colonization and invasive disease.

  • Citation: Schneewind O, Missiakas D. 2019. Sortases, Surface Proteins, and Their Roles in Disease and Vaccine Development. Microbiol Spectrum 7(1):PSIB-0004-2018. doi:10.1128/microbiolspec.PSIB-0004-2018.

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/content/journal/microbiolspec/10.1128/microbiolspec.PSIB-0004-2018
2019-02-08
2019-08-18

Abstract:

Sortases cleave short peptide motif sequences at the C-terminal end of secreted surface protein precursors and either attach these polypeptides to the peptidoglycan of Gram-positive bacteria or promote their assembly into pilus structures that are also attached to peptidoglycan. Sortase A, the enzyme first identified in the human pathogen , binds LPXTG motif sorting signals, cleaves between threonine (T) and glycine (G) residues, and forms an acyl enzyme between its active-site cysteine thiol and the carboxyl group of threonine (T). Sortase A acyl enzyme is relieved by the nucleophilic attack of the cross bridge amino group within lipid II, thereby generating surface protein linked to peptidoglycan precursor. Such products are subsequently incorporated into the cell wall envelope by enzymes of the peptidoglycan synthesis pathway. Surface proteins linked to peptidoglycan may be released from the bacterial envelope to diffuse into host tissues and fulfill specific biological functions. sortase A is essential for host colonization and for the pathogenesis of invasive diseases. Staphylococcal sortase-anchored surface proteins fulfill key functions during the infectious process, and vaccine-induced antibodies targeting surface proteins may provide protection against . Alternatively, small-molecule inhibitors of sortase may be useful agents for the prevention of colonization and invasive disease.

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FIGURE 1

Sortase-mediated anchoring to the cell wall envelope of using SpA as a model substrate. Drawing to illustrate the primary structure of the SpA precursor with its N-terminal signal peptide and signal peptidase cleavage site, the five immunoglobulin binding domains (IgBDs), region X (Xr) LysM domain, and C-terminal LPXTG motif sorting signal with cleavage site for sortase A. Cell wall SpA is linked to peptidoglycan via an amide bond between the carboxyl group of the C-terminal threonine and the amino group of the pentaglycine cross bridge. Released SpA is liberated from the cell wall envelope via the action of several murein hydrolases. Drawing to illustrate secretion of SpA precursor, sortase-mediated cleavage of SpA precursor and acyl enzyme formation, resolution of the acyl enzyme by lipid II to generate SpA linked to lipid II, incorporation of SpA into the cell wall via the transpeptidation and transglycosylation reaction, and release of SpA from the cell wall envelope by murein hydrolases. Released SpA bears the overall structure -Ala–-iGln–-Lys(SpA-LPET-Gly)–-AlaGly.

Source: microbiolspec February 2019 vol. 7 no. 1 doi:10.1128/microbiolspec.PSIB-0004-2018
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Image of FIGURE 2
FIGURE 2

Biological functions of staphylococcal protein A (SpA). and its antibiotic-resistant isolates (MRSA) harbor SpA in the cell wall envelope or released into the extracellular milieu (released SpA). Cell wall SpA binds Fcγ of human and animal IgG (green segment within blue IgG) and blocks the effector functions of antibodies, thereby preventing opsonophagocytic killing (OPK) of MRSA by immune cells through interference with complement (CR1) and Fcγ receptors (FcγRs). Released SpA cross-links V3-clonal B cell receptors (V3-BCR on the surface of B cells), triggering B cell proliferation and secretion of V3-clonal IgM and IgG (pink segments within blue IgG) without antigen specificity for . This B cell superantigen activity (BCSA) of SpA produces irrelevant V3-clonal IgG and prevents the establishment of protective immunity against . Drawing to illustrate the primary structure of human IgG with variable (V and V) and conserved (C, C1, C2, and C3) light (L) and heavy (H) chains, their antigen-binding paratope (Ag), V3, and Fcγ domains. SpA binding sites at V3 heavy chains and Fcγ are in pink and green, respectively.

Source: microbiolspec February 2019 vol. 7 no. 1 doi:10.1128/microbiolspec.PSIB-0004-2018
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Tables

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TABLE 1

cell wall-anchored surface proteins

Source: microbiolspec February 2019 vol. 7 no. 1 doi:10.1128/microbiolspec.PSIB-0004-2018

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