Peptide length and folding state govern the capacity of staphylococcal β‐type phenol‐soluble modulins to activate human formyl‐peptide receptors 1 or 2

[摘要] Moststaphylococciproduceshortα‐typePSMsandabouttwiceaslongβ‐typePSMsthatarepotentleukocyteattractantsandtoxins.PSMsareusuallysecretedwiththeN‐terminalformylgroupbutareonlyweakagonistsfortheleukocyteFPR1.Instead,theFPR1‐relatedFPR2sensesPSMsefficientlyandiscrucialforleukocyterecruitmentininfection.WhichstructuralfeaturesdistinguishFPR1fromFPR2ligandshasremainedelusive.Toanalyzewhichpeptidepropertiesmaygovernthecapacitiesofβ‐typePSMstoactivateFPRs,full‐lengthandtruncatedvariantsofsuchpeptidesfromStaphylococcusaureus,Staphylococcusepidermidis,andStaphylococcuslugdunensisweresynthesized.FPR2activationwasobservedevenforshortN‐orC‐terminalβ‐typePSMvariantsoncetheywerelongerthan18aa,andthisactivityincreasedwithlength.Incontrast,theshortesttestedpeptideswerepotentFPR1agonists,andthispropertydeclinedwithincreasingpeptidelength.Whereasfull‐lengthβ‐typePSMsformedα‐helicesandexhibitednoFPR1‐specificactivity,thetruncatedpeptideshadless‐stablesecondarystructures,wereweakagonistsforFPR1,andrequiredN‐terminalformyl‐methionineresiduestobeFPR2agonists.Together,thesedatasuggestthatFPR1andFPR2haveopposedligandpreferences.Short,flexiblePSMstructuresmayfavorFPR1butnotFPR2activation,whereaslongerpeptideswithα‐helical,amphipathicpropertiesarestrongFPR2butonlyweakFPR1agonists.Thesefindingsshouldhelptounraveltheligandspecificitiesof2criticalhumanPRRs,andtheymaybeimportantfornew,anti‐infectiveandanti‐inflammatorystrategies...

[学科分类] 生理学

[关键词] G‐protein‐coupled receptors;α‐helical peptides;neutrophils