Peptide length and folding state govern the capacity of staphylococcal β-type phenol-soluble modulins to activate human formyl-peptide receptors 1 or 2.
Most staphylococci produce short α-type PSMs and about twice as long β-type PSMs that are potent leukocyte attractants and toxins. PSMs are usually secreted with the N-terminal formyl group but are only weak agonists for the leukocyte FPR1. Instead, the FPR1-related FPR2 senses PSMs efficiently and is crucial for leukocyte recruitment in infection. Which structural features distinguish FPR1 from FPR2 ligands has remained elusive. To analyze which peptide properties may govern the capacities of β-type PSMs to activate FPRs, full-length and truncated variants of such peptides from Staphylococcus aureus, Staphylococcus epidermidis, and Staphylococcus lugdunensis were synthesized. FPR2 activation was observed even for short N- or C-terminal β-type PSM variants once they were longer than 18 aa, and this activity increased with length. In contrast, the shortest tested peptides were potent FPR1 agonists, and this property declined with increasing peptide length. Whereas full-length β-type PSMs formed α-helices and exhibited no FPR1-specific activity, the truncated peptides had less-stable secondary structures, were weak agonists for FPR1, and required N-terminal formyl-methionine residues to be FPR2 agonists. Together, these data suggest that FPR1 and FPR2 have opposed ligand preferences. Short, flexible PSM structures may favor FPR1 but not FPR2 activation, whereas longer peptides with α-helical, amphipathic properties are strong FPR2 but only weak FPR1 agonists. These findings should help to unravel the ligand specificities of 2 critical human PRRs, and they may be important for new, anti-infective and anti-inflammatory strategies.
*Interfaculty Institute of Microbiology and Infection Medicine, Cellular and Molecular Microbiology Division, University of Tübingen, Germany; and Max Planck Institute for Developmental Biology, Department I, Tübingen, Germany dorothee.kretschmer@med.uni-tuebingen.de.
Dorothee
D
Kretschmer
*Interfaculty Institute of Microbiology and Infection Medicine, Cellular and Molecular Microbiology Division, University of Tübingen, Germany; and Max Planck Institute for Developmental Biology, Department I, Tübingen, Germany.
Maren
M
Rautenberg
*Interfaculty Institute of Microbiology and Infection Medicine, Cellular and Molecular Microbiology Division, University of Tübingen, Germany; and Max Planck Institute for Developmental Biology, Department I, Tübingen, Germany.
Dirk
D
Linke
*Interfaculty Institute of Microbiology and Infection Medicine, Cellular and Molecular Microbiology Division, University of Tübingen, Germany; and Max Planck Institute for Developmental Biology, Department I, Tübingen, Germany.
Andreas
A
Peschel
D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001427:Bacterial Toxins / Q000737:chemistry* / Q000494:pharmacology; D039481:CD11b Antigen / Q000096:biosynthesis / Q000235:genetics; D020013:Calcium Signaling / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003603:Cytotoxins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018922:HL-60 Cells; D006460:Hemolysin Proteins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D008969:Molecular Sequence Data; D009239:N-Formylmethionine / Q000737:chemistry; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017510:Protein Folding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D044042:Receptors, Formyl Peptide / Q000187:drug effects* / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000187:drug effects* / Q000378:metabolism; D013211:Staphylococcus aureus / Q000737:chemistry; D013212:Staphylococcus epidermidis / Q000737:chemistry; D057787:Staphylococcus lugdunensis / Q000737:chemistry; D013329:Structure-Activity Relationship
D001426:Bacterial Proteins; D001427:Bacterial Toxins; D039481:CD11b Antigen; D003603:Cytotoxins; C469986:FPR1 protein, human; C105101:FPR2 protein, human; D006460:Hemolysin Proteins; C509295:ITGAM protein, human; D016209:Interleukin-8; D010446:Peptide Fragments; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C103340:SLUSH protein, Staphylococcus sp.; C025971:staphylococcal delta toxin; D009239:N-Formylmethionine
G-protein-coupled receptors; neutrophils; α-helical peptides