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Insight into structure‐function relationship in phenol‐soluble modulins using an alanine screen of the phenol‐soluble modulin (PSM) α3 peptide
Author(s) -
Cheung Gordon Y. C.,
Kretschmer Dorothee,
Queck Shu Y.,
Joo HwangSoo,
Wang Rong,
Duong Anthony C.,
Nguyen Thuan H.,
Bach ThanhHuy L.,
Porter Adeline R.,
DeLeo Frank R.,
Peschel Andreas,
Otto Michael
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-232041
Subject(s) - chemistry , proinflammatory cytokine , biofilm , receptor , cytolysis , amino acid , innate immune system , staphylococcus aureus , alanine , antimicrobial peptides , peptide , biochemistry , microbiology and biotechnology , biology , cytotoxicity , bacteria , immunology , in vitro , inflammation , genetics
Phenol‐soluble modulins (PSMs) are a family of peptides with multiple functions in staphylococcal pathogenesis. To gain insight into the structural features affecting PSM functions, we analyzed an alanine substitution library of PSMα3, a strongly cytolytic and proinflammatory PSM of Staphylococcus aureus with a significant contribution to S. aureus virulence. Lysine residues were essential for both receptor‐dependent proinflammatory and receptor‐independent cytolytic activities. Both phenotypes also required additional structural features, with the C terminus being crucial for receptor activation. Biofilm formation was affected mostly by hydrophobic amino acid positions, suggesting that the capacity to disrupt hydrophobic interactions is responsible for the effect of PSMs on biofilm structure. Antimicrobial activity, absent from natural PSMα3, could be created by the exchange of large hydrophobic side chains, indicating that PSMα3 has evolved to exhibit cytolytic rather than antimicrobial activity. In addition to gaining insight into the structure‐function relationship in PSMs, our study identifies nontoxic PSMα3 derivatives for active vaccination strategies and lays the foundation for future efforts aimed to understand the biological role of PSM recognition by innate host defense.—Cheung, G. Y., Kretschmer, D., Queck, S. Y., Joo, H.‐S., Wang, R., Duong, A. C., Nguyen, T. H., Bach, T.‐H., Porter, A. R., DeLeo, F. R., Peschel, A., Otto, M. Insight into structure‐function relationship in phenol‐soluble modulins using an alanine screen of the phenol‐soluble modulin (PSM) α3 peptide. FASEB J . 28, 153–161 (2014). www.fasebj.org