Structural Basis for Sialoglycan Binding by the Streptococcus sanguinis SrpA Adhesin

Bensing, Barbara A.; Loukachevitch, Lioudmila V.; McCulloch, K.M.; Yu, Hai; Vann, Kendra R.; Wawrzak, Z.; Anderson, Spencer; Chen, Xi; Sullam, Paul M.; Iverson, T.M.

doi:10.1074/jbc.m115.701425

Cited by 38 publications

(73 citation statements)

References 34 publications

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“…SRRPs contain two glycosylated serine-rich repeat (SRR) regions which comprise the majority of the protein, a cell wall anchor, and one or two nonrepeat regions within the N-terminal region (16,52). The nonrepeat regions of SRRPs mediate adherence, and diversity in the modular structure of these regions accounts for the different receptors for these proteins, including sialic acid, keratins, and fibrinogen (16,20,23,35,40,44,45,51,(54)(55)(56). BLAST searches identified no significant sequence similarity between the nonrepeat region of S. oralis SRRP and other available sequences.…”

Section: Resultsmentioning

confidence: 99%

“…During completion of this study, Bensing et al identified a threonine-arginine (Thr-Arg) motif conserved in sialoglycan-binding SRRPs that is required for orienting the sialic acid residue (20,56). This motif is required for efficient glycan binding, platelet binding, and full virulence in the rat model of infective endocarditis (20,56). These residues are conserved in ATCC 10557 Fap1, and mutagenesis of the arginine residue significantly reduced adherence, further supporting the hypothesis that Fap1 acts as an adhesin binding sialic acid (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Streptococcus oralis Neuraminidase Modulates Adherence to Multiple Carbohydrates on Platelets

et al. 2017

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Adherence to host surfaces is often mediated by bacterial binding to surface carbohydrates. Although it is widely appreciated that some bacterial species express glycosidases, previous studies have not considered whether bacteria bind to multiple carbohydrates within host glycans as they are modified by bacterial glycosidases. Streptococcus oralis is a leading cause of subacute infective endocarditis. Binding to platelets is a critical step in disease; however, the mechanisms utilized by S. oralis remain largely undefined. Studies revealed that S. oralis, like Streptococcus gordonii and Streptococcus sanguinis, binds platelets via terminal sialic acid. However, unlike those organisms, S. oralis produces a neuraminidase, NanA, which cleaves terminal sialic acid. Further studies revealed that following NanA-dependent removal of terminal sialic acid, S. oralis bound exposed ␤-1,4-linked galactose. Adherence to both these carbohydrates required Fap1, the S. oralis member of the serine-rich repeat protein (SRRP) family of adhesins. Mutation of a conserved residue required for sialic acid binding by other SRRPs significantly reduced platelet binding, supporting the hypothesis that Fap1 binds this carbohydrate. The mechanism by which Fap1 contributes to ␤-1,4-linked galactose binding remains to be defined; however, binding may occur via additional domains of unknown function within the nonrepeat region, one of which shares some similarity with a carbohydrate binding module. This study is the first demonstration that an SRRP is required to bind ␤-1,4-linked galactose and the first time that one of these adhesins has been shown to be required for binding of multiple glycan receptors.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Streptococcus oralis Neuraminidase Modulates Adherence to Multiple Carbohydrates on Platelets

et al. 2017

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“…8). Validating this binding mode, we previously showed that Thr 346 and Arg 347 are important for the interaction between SrpA and platelets via site-directed mutagenesis 18 . The electron densities for additional sugars were almost universally weaker (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In recent work, we combined X-ray crystallography with functional binding measurements to identify the structural basis for sialoglycan binding by both SrpA BR 18 and GspB BR 19, 20 . These studies included a high-resolution costructure of SrpA BR bound to a non-human N -glycolylneuraminic acid (Neu5Gc)-based sialyl galactoside disaccharide 18 .…”

Section: Introductionmentioning

confidence: 99%

“…These studies included a high-resolution costructure of SrpA BR bound to a non-human N -glycolylneuraminic acid (Neu5Gc)-based sialyl galactoside disaccharide 18 . Here, we further explore the binding repertoire of SrpA BR , using a range of Neu5Ac-based α2-3 linked sialoglycans that are low-affinity ligands: sialyl-T antigen (Neu5Acα2–3Galβ1–3GalNAc; Fig.…”

Section: Introductionmentioning

confidence: 99%

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Structures of the Streptococcus sanguinis SrpA Binding Region with Human Sialoglycans Suggest Features of the Physiological Ligand

Loukachevitch

Bensing

et al. 2016

Biochemistry

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Streptococcus sanguinis is a leading cause of bacterial infective endocarditis, a life threatening infection of heart valves. S. sanguinis binds to human platelets with high avidity, and this adherence is likely to enhance virulence. Previous studies suggest that a serine-rich repeat adhesin termed SrpA mediates the binding of S. sanguinis to human platelets via its interaction with sialoglycans on the receptor GPIbα. However, in vitro binding assays between SrpA and defined sialoglycans failed to identify specific high-affinity ligands. To better understand the interaction between SrpA and human platelets, we determined cocrystal structures of the SrpA sialoglycan binding region (SrpABR) with five low-affinity ligands: three sialylated trisaccharides (sialyl-T antigen, 3'-sialyllactose, and 3'-sialyl-N-acetyllactosamine), a sialylated tetrasaccharide (sialyl-LewisX) and a sialyl galactose disaccharide component common to these sialoglyans. We then combined structural analysis with mutagenesis to further determine whether our observed interactions between SrpABR and glycans are important for binding to platelets and to better map the binding site for the physiological receptor. We found that the sialoglycan binding site of SrpABR is significantly larger than the sialoglycans cocrystallized in this study, which suggests that SrpA binding to platelets is either multivalent or occurs via a larger, disialylated glycan.

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Platelets

Levin

2017

Inflammation - From Molecular and Cellular Mechanisms to the Clinic

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Structural Basis for Sialoglycan Binding by the Streptococcus sanguinis SrpA Adhesin

Cited by 38 publications

References 34 publications

Streptococcus oralis Neuraminidase Modulates Adherence to Multiple Carbohydrates on Platelets

Streptococcus oralis Neuraminidase Modulates Adherence to Multiple Carbohydrates on Platelets

Structures of the Streptococcus sanguinis SrpA Binding Region with Human Sialoglycans Suggest Features of the Physiological Ligand

Platelets

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