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

Lioudmila V. Loukachevitch, Barbara A. Bensing, Hai Yu, Jie Zeng, Xi Chen, Paul M. Sullam, T. M. Iverson

Research output: Contribution to journalArticle

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Abstract

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 with SrpA and defined sialoglycans failed to identify specific high-affinity ligands. To improve our understanding of 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 binding of SrpA to platelets either is multivalent or occurs via a larger, disialylated glycan.

Original languageEnglish (US)
Pages (from-to)5927-5937
Number of pages11
JournalBiochemistry
Volume55
Issue number42
DOIs
StatePublished - Oct 25 2016

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Platelets
Streptococcus
Blood Platelets
Ligands
Polysaccharides
Binding Sites
Trisaccharides
Bacterial Endocarditis
Mutagenesis
Disaccharides
Viral Tumor Antigens
Heart Valves
Endocarditis
Galactose
Structural analysis
Serine
Virulence
Assays
Infection

ASJC Scopus subject areas

  • Biochemistry

Cite this

Structures of the Streptococcus sanguinis SrpA Binding Region with Human Sialoglycans Suggest Features of the Physiological Ligand. / Loukachevitch, Lioudmila V.; Bensing, Barbara A.; Yu, Hai; Zeng, Jie; Chen, Xi; Sullam, Paul M.; Iverson, T. M.

In: Biochemistry, Vol. 55, No. 42, 25.10.2016, p. 5927-5937.

Research output: Contribution to journalArticle

Loukachevitch, Lioudmila V. ; Bensing, Barbara A. ; Yu, Hai ; Zeng, Jie ; Chen, Xi ; Sullam, Paul M. ; Iverson, T. M. / Structures of the Streptococcus sanguinis SrpA Binding Region with Human Sialoglycans Suggest Features of the Physiological Ligand. In: Biochemistry. 2016 ; Vol. 55, No. 42. pp. 5927-5937.
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