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Tandem sialoglycan-binding modules in a Streptococcus sanguinis serine-rich repeat adhesin create target dependent avidity effects


Stubbs HEHaley , Bensing BABarbara , Yamakawa IIzumi , Sharma PPankaj , Yu HHai , Chen XXi , Sullam PMPaul , Iverson TMTina . Journal of Biological Chemistry. 2020 8 20; ().


Siglec-like domains of streptococcal serine-rich repeat (SRR) adhesins recognize sialylated glycans on human salivary, platelet, and plasma glycoproteins via a “YTRY” sequence motif. The SRR adhesin from Streptococcus sanguinis strain SK1 has tandem sialoglycan-binding domains and has previously been shown to bind sialoglycans with high affinity. However, both domains contain substitutions within the canonical “YTRY” motif, making it unclear how they interact with host receptors. To identify how the S. sanguinis strain SK1 SRR adhesin affects interactions with sialylated glycans and glycoproteins, we determined high-resolution crystal structures of the binding domains alone and with purified trisaccharides. These structural studies identify that the ligands still bind at the non-canonical binding motif, but with fewer hydrogen-bonding interactions to the protein than is observed in structures of other Siglec-like adhesins. Complementary biochemical studies identify that each of the two binding domains has a different selectivity profile. Interestingly, the binding of SK1 to platelets and plasma glycoproteins identifies that the interaction to some host targets is dominated by the contribution of one binding domain, while the binding to other host receptors is mediated by both binding domains. These results provide insight into outstanding questions concerning the roles of tandem domains in targeting host receptors and suggest mechanisms for how pathogens can adapt to the availability of a range of related but non-identical host receptors. They further suggest that the definition of the “YTRY” motif should be changed to ϕTRX, a more rigorous description of this sialic acid-recognition motif given recent findings.