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Review
. 2014 Jan;12(1):49-62.
doi: 10.1038/nrmicro3161.

Adhesion, invasion and evasion: the many functions of the surface proteins of Staphylococcus aureus

Timothy J Foster  1 , Joan A Geoghegan  1 , Vannakambadi K Ganesh  2 , Magnus Höök  2
Affiliations
Review

Adhesion, invasion and evasion: the many functions of the surface proteins of Staphylococcus aureus

Timothy J Foster et al. Nat Rev Microbiol. 2014 Jan.

Abstract

Staphylococcus aureus is an important opportunistic pathogen and persistently colonizes about 20% of the human population. Its surface is 'decorated' with proteins that are covalently anchored to the cell wall peptidoglycan. Structural and functional analysis has identified four distinct classes of surface proteins, of which microbial surface component recognizing adhesive matrix molecules (MSCRAMMs) are the largest class. These surface proteins have numerous functions, including adhesion to and invasion of host cells and tissues, evasion of immune responses and biofilm formation. Thus, cell wall-anchored proteins are essential virulence factors for the survival of S. aureus in the commensal state and during invasive infections, and targeting them with vaccines could combat S. aureus infections.

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Conflict of interest statement

Competing interests statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1. Functions of CWA proteins of S. aureus
The cell wall-anchored (CWA) protein iron-regulated surface determinant (Isd) binds haemoglobin and extracts and transports haem across the cell wall and membrane into the cytoplasm, where iron is released. Protein A acts as a superantigen for B lymphocytes and disrupts adaptive immune responses and immunological memory. Phagocytosis by neutrophils is inhibited by the binding of CWA proteins to IgG and other plasma proteins, by reducing the level of — or access by — neutrophil receptors to the complement opsonin C3b and, if engulfed, by inhibiting the oxidative burst. CWA proteins promote adhesion of Staphylococcus aureus to the extracellular matrix, to the surface of host cells and to biomaterial surfaces that are conditioned by the deposition of plasma proteins. Interactions between CWA proteins on adjacent cells contribute to the accumulation phase of biofilm formation. CWA proteins directly or indirectly interact with integrins and promote the invasion of non-phagocytic host cells. Intracellular bacteria can cause host cell apoptosis or necrosis, or they can enter a non-disruptive semi-dormant state known as small colony variants. By binding to and activating tumour necrosis factor receptor 1 (TNFR1) on host epithelial cells, protein A triggers the synthesis of cytokines (for example, interleukin-6 (IL-6)) and causes disruptive inflammation, which contributes to pathogenesis. NF-κB, nuclear factor-κB.
Figure 2
Figure 2. Classification of CWA proteins on the basis of structural motifs
The primary translation products of all cell wall-anchored (CWA) proteins contain a signal sequence at the amino terminus and a wall-spanning region and sorting signal at the carboxyl terminus. The CWA proteins that are depicted are those for which structural analysis has facilitated classification into four distinct groups. a | Microbial surface component 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 of Staphylococcus aureus and SdrF of Staphylococcus epidermidis contain additional BSDR repeats that are located between the A domain and the serine–aspartate repeat R region. The N-terminal A region contains three separately folded domains, which are known as N1, N2 and N3. Structurally, N2 and N3 form IgG-like folds that bind ligands by the ‘dock, lock and latch’ (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 to 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 BCNA repeats. b | 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 haemoglobin or haem. 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. c | 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 non-repetitive Xc region. d | G5–E repeat family. The alternating repeats of the G5 and E domains of S. aureus surface protein G (SasG) from S. aureus and accumulation-associated protein (Aap) from S. epidermidis 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.
Figure 3
Figure 3. Mechanisms of ligand binding by MSCRAMM proteins
a | Dock, lock and latch (DLL) mechanism. The A region of the microbial surface component recognizing adhesive matrix molecule (MSCRAMM) protein in its open apo form has a wide trench between the N2 and N3 subdomains (apo serine–aspartate repeat-containing protein (SdrG); Protein Data Bank (PDB) reference: 1R19). The ligand peptide (purple) inserts into this trench and the MSCRAMM protein undergoes conformational changes to a closed form and locks the ligand in place (SdrG–ligand complex; PDB reference: 1R17). In the apo form, the disordered carboxy-terminal extension of the N3 subdomain is not part of the crystal structure. After ligand binding, this region forms the lock (blue) and the latch (red), thus locking the ligand in place. b | Collagen hug mechanism. In the apo form, collagen adhesin (Cna) is in an equilibrium between an open and closed form. The crystal structure shows the closed form with the empty ligand-binding trench covered by the lock (blue) (apo Cna; PDB reference: 2F68). The latch peptide (red) has undergone β-strand complementation with the latching sequence in N1. In the open form (not shown), the rope-like collagen triple helix docks into a trench that is located between the N1 and N2 subdomains. The conformational change back to the closed form captures (or ‘hugs’) the ligand (purple) using residues in the lock region (blue) (Cna–collagen complex; PDB reference: 2F6A).
Figure 4
Figure 4. Roles of CWA proteins in biofilm formation
Cell wall-anchored (CWA) proteins promote attachment to surfaces that have been conditioned with host plasma proteins. Extracellular DNA that is released by autolysins can promote attachment to unconditioned surfaces. When the A domain of accumulation-associated protein (Aap) of Staphylococcus epidermidis or Staphylococcus aureus surface protein G (SasG) of S. aureus is removed, the G5–E repeats on adjacent cells can twist around each other in a Zn2+-dependent manner to promote cell–cell aggregation and biofilm accumulation. Fibronectin-binding proteins (FnBPs) and other surface proteins promote accumulation either by homophilic protein–protein interactions or by binding to other ligands on neighbouring cells.
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