4.8 Article

Structural basis for inhibition of TLR2 by staphylococcal superantigen-like protein 3 (SSL3)

出版社

NATL ACAD SCIENCES
DOI: 10.1073/pnas.1502026112

关键词

S. aureus; Toll-like receptor; immune evasion; innate immunity; crystal structure

资金

  1. Dutch Top Institute Pharma Project [D1-101]
  2. ECHO Grant from Council of Chemical Sciences of the Netherlands Organization for Scientific Research [700.58.006]
  3. ManiFold Project from European Union [317371]
  4. ZonMw from Netherlands Organization for Health Research and Development [205200004]

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Toll-like receptors (TLRs) are crucial in innate recognition of invading micro-organisms and their subsequent clearance. Bacteria are not passive bystanders and have evolved complex evasion mechanisms. Staphylococcus aureus secretes a potent TLR2 antagonist, staphylococcal superantigen-like protein 3 (SSL3), which prevents receptor stimulation by pathogen-associated lipopeptides. Here, we present crystal structures of SSL3 and its complex with TLR2. The structure reveals that formation of the specific inhibitory complex is predominantly mediated by hydrophobic contacts between SSL3 and TLR2 and does not involve interaction of TLR2-glycans with the conserved Lewis(X) binding site of SSL3. In the complex, SSL3 partially covers the entrance to the lipopeptide binding pocket in TLR2, reducing its size by similar to 50%. We show that this is sufficient to inhibit binding of agonist Pam(2)CSK(4) effectively, yet allows SSL3 to bind to an already formed TLR2-Pam(2)CSK(4) complex. The binding site of SSL3 overlaps those of TLR2 dimerization partners TLR1 and TLR6 extensively. Combined, our data reveal a robust dual mechanism in which SSL3 interferes with TLR2 activation at two stages: by binding to TLR2, it blocks ligand binding and thus inhibits activation. Second, by interacting with an already formed TLR2-lipopeptide complex, it prevents TLR heterodimerization and downstream signaling.

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