Crystal Structure of the V-region of Streptococcus mutans Antigen I/II at 2.4Å Resolution Suggests a Sugar Preformed Binding Site

Troffer-Charlier, N.; Ogier, Joëlle; Moras, Dino; Cavarelli, Jean

doi:10.1016/s0022-2836(02)00025-6

Cited by 57 publications

(70 citation statements)

References 46 publications

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“…Recently, the crystal structure of a recombinant protein spanning the variable (V) region of antigen I/II (SR) from S. mutans serotype f strain OMZ 175 has been determined (39). While this recombinant protein does not encompass the A-and P-region binding sites defined in our studies, it does include some flanking alanine-rich and proline-rich sequences.…”

Section: Discussionmentioning

confidence: 94%

Peptide Mapping of a Novel Discontinuous Epitope of the Major Surface Adhesin from Streptococcus mutans

Dolleweerd

Kelly

Chargelegue

et al. 2004

Journal of Biological Chemistry

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Guy's 13 is a mouse monoclonal antibody that specifically recognizes the major cell-surface adhesion protein SA I/II of Streptococcus mutans, one of the major causative agents of dental caries. Passive immunization with Guy's 13 prevents bacterial colonization in humans. To help elucidate the mechanism of prevention of colonization conferred by this antibody, the SA I/II epitope recognized by Guy's 13 was investigated. It was previously established that the epitope is conformational, being assembled from two non-contiguous regions of SA I/II. In the current study, using recombinant fragments of SA I/II and, ultimately, synthetic peptides, the discontinuous epitope was localized to residues 170 -218 and 956 -969. This work describes the mapping of a novel discontinuous epitope that requires an interaction between each determinant in order for epitope assembly and recognition by antibody to take place. Guy's 13 binds to the assembled epitope but not to these individual epitope fragments. The assembled epitope results from the interaction between the individual antigenic determinants and can be formed by mixing together determinants present on separate polypeptide chains. The data are consistent with one of the epitope fragments adopting a polyproline II-like helical conformation.

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Section: Discussionmentioning

confidence: 94%

Peptide Mapping of a Novel Discontinuous Epitope of the Major Surface Adhesin from Streptococcus mutans

Dolleweerd

Kelly

Chargelegue

et al. 2004

Journal of Biological Chemistry

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“…BspA-V adopts a fold that is distinct from those reported for other AgI/II family polypeptide V domains (11,12). This consists of two anti-parallel ␤-sheets, S1 and S2, comprising 5 and 7 strands, respectively (Fig.…”

Section: The Bspa Variable Domain Possesses a ␤-Sandwich Fold That Ismentioning

confidence: 90%

“…The N terminus forms a stabilizing scaffold by wrapping behind the base of the stalk (10). Crystal structures of the V regions of SpaP and SspB have revealed a common architecture consisting of a lectin-like fold with a putative binding cleft (11,12). The structure of the C-terminal subdomains C1, C2, and C3 has also been elucidated by x-ray crystallography and found to consist of ␤-sandwich domains stabilized by isopeptide bonds (13)(14)(15)(16).…”

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confidence: 99%

Structural and Functional Analysis of Cell Wall-anchored Polypeptide Adhesin BspA in Streptococcus agalactiae

Rego

Heal

Pidwill

et al. 2016

Journal of Biological Chemistry

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Streptococcus agalactiae (group B Streptococcus, GBS) is the predominant cause of early-onset infectious disease in neonates and is responsible for life-threatening infections in elderly and immunocompromised individuals. Clinical manifestations of GBS infection include sepsis, pneumonia, and meningitis. Here, we describe BspA, a deviant antigen I/II family polypeptide that confers adhesive properties linked to pathogenesis in GBS. Heterologous expression of BspA on the surface of the non-adherent bacterium Lactococcus lactis confers adherence to scavenger receptor gp340, human vaginal epithelium, and to the fungus Candida albicans. Complementary crystallographic and biophysical characterization of BspA reveal a novel ␤-sandwich adhesion domain and unique asparagine-dependent super-helical stalk. Collectively, these findings establish a new bacterial adhesin structure that has in effect been hijacked by a pathogenic Streptococcus species to provide competitive advantage in human mucosal infections. Streptococcus agalactiae (group B Streptococcus (GBS)4 ) is a commensal of the gastrointestinal tract and part of the normal microbiota of the female rectovaginal tract, where it is carried asymptomatically by ϳ10 -40% of women of childbearing age (1). However, as an opportunistic pathogen, GBS is the leading cause of neonatal meningitis and sepsis in the developed world. The predominant route by which GBS is transmitted to infants is from the mother, either during birth or following breach of the placental barrier in utero. Antenatal GBS screening strategies are therefore commonly used to identify colonized women, who then receive antimicrobial prophylaxis. Nevertheless, GBS remains a major cause of morbidity and mortality in infants worldwide (2).Because maternal GBS colonization is the primary risk factor for vertical transmission of neonatal infection (3), there has been considerable focus on the mechanisms underlying GBS colonization of the female genitourinary (GU) tract. A number of putative colonization determinants have been identified, including the following: ␣C protein, mediating entry of GBS into cervical epithelial cells (4); pili, shown to contribute to vaginal attachment (5); and Srr-1, which binds keratin-4 (5) and fibrinogen (6) on the surface of vaginal epithelium. In addition, GBS expresses numerous extracellular matrix-binding proteins, including C5a peptidase (ScpB) and FbsA, which may promote attachment to mucosal tissues of the GU tract (7).Antigen I/II (AgI/II) family polypeptide adhesins are found widely across the Streptococcus genus and have been best characterized for those streptococci indigenous to the oral cavity (8). In silico analyses have recently revealed the presence of genes encoding AgI/II family polypeptides in GBS, which we have designated here group B Streptococcus surface proteins (Bsp). These proteins conform to a conserved primary structure consisting of seven distinct regions (Fig. 1). The N-terminal region comprises a signal (leader) peptide, an N-terminal domain, and an ...

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“…The resulting electron density map had clear interpretable densities for the helical repeat regions, and were then built with Coot (46). Residues 495-828 of the A 1 VP 3 structures were highly similar to the solved AgI/II V-region structure (12) (average rmsd of 0.431 Å). The final Rfactor/Rfree of the models were 18.1/22.2 (native) and 19.0/22.8 (fructose co-crystal).…”

Section: Methodsmentioning

confidence: 98%

“…Nested between the A and P repeats is a segment commonly referred to as the V or variable region, which contains within it a stretch of ∼100 amino acids where most of the sequence variation among S. mutans AgI/II molecules is clustered (11). The crystal structure of the V region adopts a globular β-stranded "super-sandwich" fold (12). Finally, the carboxy terminus contains the LPxTG sortase motif for covalent anchorage to the cell wall (13).…”

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confidence: 99%

Elongated fibrillar structure of a streptococcal adhesin assembled by the high-affinity association of α- and PPII-helices

Larson

Rajashankar

Patel

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

175

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Streptococcus mutans antigen I/II (AgI/II) is a cell surface-localized protein adhesin that interacts with salivary components within the salivary pellicle. AgI/II contributes to virulence and has been studied as an immunological and structural target, but a fundamental understanding of its underlying architecture has been lacking. Here we report a high-resolution (1.8 Å) crystal structure of the A 3 VP 1 fragment of S. mutans AgI/II that demonstrates a unique fibrillar form (155 Å) through the interaction of two noncontiguous regions in the primary sequence. The A 3 repeat of the alanine-rich domain adopts an extended α-helix that intertwines with the P 1 repeat polyproline type II (PPII) helix to form a highly extended stalk-like structure heretofore unseen in prokaryotic or eukaryotic protein structures. Velocity sedimentation studies indicate that fulllength AgI/II that contains three A/P repeats extends over 50 nanometers in length. Isothermal titration calorimetry revealed that the high-affinity association between the A 3 and P 1 helices is enthalpically driven. Two distinct binding sites on AgI/II to the host receptor salivary agglutinin (SAG) were identified by surface plasmon resonance (SPR). The current crystal structure reveals that AgI/II family proteins are extended fibrillar structures with the number of alanine-and proline-rich repeats determining their length.bacterial adhesion | dental caries | Streptococcus | x-ray crystallography | fibrous proteins S treptococcus mutans is the causative agent of human dental caries (1) and its protein adhesin antigen I/II (AgI/II) is a known target of protective immunity (2). AgI/II family molecules are expressed by numerous oral streptococci (3) and homologs have also been identified in the invasive pathogens Streptococcus pyogenes and Streptococcus agalactiae (4) (Fig. S1). In addition to mediating adhesion to the tooth surface (5), AgI/II influences biofilm formation (6), promotes collagen-dependent bacterial invasion of dentin (7), and mediates adherence to human epithelial cells (8). Elimination of AgI/II results in decreased virulence (9), but despite three decades of study, a mechanistic understanding of the functional properties of the molecule has been stymied by a lack of understanding of its structure.Originally identified as AgI/II (10) (also called P1, PAc, or SpaP), members of this protein family contain between 1310 and 1653 amino acids (aa) beginning with an amino-terminal signal motif that directs secretion, followed by the A, V, and P regions (Fig. 1A). The A region typically consists of 3-4 alanine-rich repeats (82 residues each) with 23-30% alanine content. The P region has 3-4 proline-rich repeats (39 residues each) with ∼35% proline content. Nested between the A and P repeats is a segment commonly referred to as the V or variable region, which contains within it a stretch of ∼100 amino acids where most of the sequence variation among S. mutans AgI/II molecules is clustered (11). The crystal structure of the V region adopts a globular β-s...

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Crystal Structure of the V-region of Streptococcus mutans Antigen I/II at 2.4Å Resolution Suggests a Sugar Preformed Binding Site

Cited by 57 publications

References 46 publications

Peptide Mapping of a Novel Discontinuous Epitope of the Major Surface Adhesin from Streptococcus mutans

Peptide Mapping of a Novel Discontinuous Epitope of the Major Surface Adhesin from Streptococcus mutans

Structural and Functional Analysis of Cell Wall-anchored Polypeptide Adhesin BspA in Streptococcus agalactiae

Elongated fibrillar structure of a streptococcal adhesin assembled by the high-affinity association of α- and PPII-helices

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