Abstract
Staphylococcus aureus, a Gram-positive bacterium causes a number of devastating human diseases, such as infective endocarditis, osteomyelitis, septic arthritis and sepsis. S. aureus SraP, a surface-exposed serine-rich repeat glycoprotein (SRRP), is required for the pathogenesis of human infective endocarditis via its ligand-binding region (BR) adhering to human platelets. It remains unclear how SraP interacts with human host. Here we report the 2.05 Å crystal structure of the BR of SraP, revealing an extended rod-like architecture of four discrete modules. The N-terminal legume lectin-like module specifically binds to N-acetylneuraminic acid. The second module adopts a β-grasp fold similar to Ig-binding proteins, whereas the last two tandem repetitive modules resemble eukaryotic cadherins but differ in calcium coordination pattern. Under the conditions tested, small-angle X-ray scattering and molecular dynamic simulation indicated that the three C-terminal modules function as a relatively rigid stem to extend the N-terminal lectin module outwards. Structure-guided mutagenesis analyses, in addition to a recently identified trisaccharide ligand of SraP, enabled us to elucidate that SraP binding to sialylated receptors promotes S. aureus adhesion to and invasion into host epithelial cells. Our findings have thus provided novel structural and functional insights into the SraP-mediated host-pathogen interaction of S. aureus.
Highlights
The serine-rich repeat glycoproteins (SRRPs) are a family of adhesins encoded by Gram-positive bacteria that mediate attachment to a variety of host cells or bacteria themselves [1]
Staphylococcus aureus is an important pathogen that causes a range of human diseases, such as infective endocarditis, osteomyelitis, septic arthritis and sepsis
As a surfaceexposed serine-rich repeat glycoprotein (SRRP), S. aureus serine-rich adhesin for binding to platelets (SraP) is involved in the pathogenesis of infective endocarditis via its ligand-binding region (BR) adhering to human platelets
Summary
The serine-rich repeat glycoproteins (SRRPs) are a family of adhesins encoded by Gram-positive bacteria that mediate attachment to a variety of host cells or bacteria themselves [1]. SRRPs typically consist of a signal peptide at the N-terminus, a short SRR (SRR1, ,50–170 residues), a ligand-binding region (BR, ,250–500 residues) followed by a much longer SRR (SRR2, ,400–4000 residues), and a C-terminal LPXTG motif anchoring to the cell wall [1]. The BRs of SRRPs from different pathogenic bacteria have varying primary sequences and bind to diverse targets from carbohydrates to proteins [1]. In addition to having highly variable sequences, the BRs from different bacteria are composed of distinct modules. The diversity of BR modules and combinations contributes to the multiple functions of SRRPs. The only four known BR structures to date have identified five distinct modules [2,3,4]. The recently reported BR structures of the two SRRP paralogs (Srr and Srr2)
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