Differential activation of polymorphisms of the formyl peptide receptor by formyl peptides.
We have investigated the role of two polymorphic sites (R190W and N192K) on the binding and activation of the formyl peptide receptor (FPR) by viral and formyl peptides. WEDWVGWI, a peptide with antiviral activity derived from the membrane proximal region of feline immunodeficiency virus, binds with high affinity to FPR. The three tryptophans in the peptide are all essential for FPR binding, just as they were essential for antiviral activity [S. Giannecchini, A. Di Fenza, A.M. D'Ursi, D. Matteucci, P. Rovero, M. Bendinelli, Antiviral activity and conformational features of an octapeptide derived from the membrane-proximal ectodomain of the feline immunodeficiency virus transmembrane glycoprotein, J. Virol. 77 (2003) 3724]. Formyl-NleWEDWVGWI behaved as a weak partial agonist with FPR W190/N192 but a stronger partial agonist with FPR R190/K192 and FPR R190/N192. Formyl-NleNleWEDWVGWI behaved as a full agonist toward all three FPRs but exhibited a much higher EC(50) with W190/N192 FPR (300+/-45 nM) than for R190/K192 FPR (40+/-3 nM) or R190/N192 (60+/-8 nM). Formyl-MYKWPWYVWL preferentially activated R190/K192 and R190/N192 FPRs by>5 fold compared to W190/N192 FPR. Formyl-MFEDAVAWF, a peptide derived from a protein in Mycobacterium avium subsp. paratuberculosis and formyl-MFTFEPFPTN, a peptide derived from the N-terminus of chemotaxis inhibitory protein of Staphylococcus aureus with an added N-terminal formyl-methionine exhibited the greatest selectivity for R190/K192 and R190/N192 FPRs with approximately 10 fold lower EC(50)s than that observed with FPR W190/N192. Thus, individuals with the W190 polymorphism may display a reduced ability to detect certain formyl peptides.
Mills
John S
JS
Montana State University, 109 Lewis Hall, Bozeman, MT 59717-3520, USA. umbmj@montana.edu
D000595:Amino Acid Sequence; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D008969:Molecular Sequence Data; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding / Q000187:drug effects; D044042:Receptors, Formyl Peptide / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
D000954:Antigens, Surface; D010446:Peptide Fragments; D044042:Receptors, Formyl Peptide; D009240:N-Formylmethionine Leucyl-Phenylalanine