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Structural changes of the ligand and of the receptor alters the receptor preference for neutrophil activating peptides starting with a formylmethionyl group
- Source :
- Biochimica et Biophysica Acta-Molecular Cell Research, Biochimica et Biophysica Acta-Molecular Cell Research, Elsevier, 2015, 1853 (1), pp.192-200. ⟨10.1016/j.bbamcr.2014.10.021⟩
- Publication Year :
- 2015
- Publisher :
- HAL CCSD, 2015.
-
Abstract
- International audience; Pathogenic Staphylococcus aureus strains produce N-formylmethionyl containing peptides, of which the tetrapeptide fMIFL is a potent activator of the neutrophil formyl peptide receptor 1 (FPR1) and the PSMα2 peptide is a potent activator of the closely related FPR2. Variants derived from these two peptide activators were used to disclose the structural determinants for receptor interaction. Removal of five amino acids from the C-terminus of PSMα2 gave rise to a peptide that had lost the receptor-independent neutrophil permeabilizing effect, whereas neutrophil activation capacity as well as its preference for FPR2 was retained. Shorter peptides, PSMα21-10 and PSMα21-5, activate neutrophils, but the receptor preference for these peptides was switched to FPR1. The fMIFL-PSM5-16 peptide, in which the N-terminus of PSMα21-16 was replaced by the sequence fMIFL, was a dual agonist for FPR1/FPR2, whereas fMIFL-PSM5-10 preferred FPR1 to FPR2. Further, an Ile residue was identified as a key determinant for interaction with FPR2. A chimeric receptor in which the cytoplasmic tail of FPR1 was replaced by the corresponding part of FPR2 lost the ability to recognize FPR1 agonists, but gained function in relation to FPR2 agonists. Taken together, our data demonstrate that the C-terminus of the PSMα2 peptide plays a critical role for its cytotoxicity, but is not essential for the receptor-mediated pro-inflammatory activity. More importantly, we show that the amino acids present in the C-terminus, which are not supposed to occupy the agonist-binding pocket in the FPRs, are of importance for the choice of receptor.
- Subjects :
- Formyl peptide
Peptide
MESH: Receptors, Formyl Peptide
MESH: Receptors, Lipoxin
Biology
Ligands
Neutrophil Activation
Formyl peptide receptor 1
Structure-Activity Relationship
03 medical and health sciences
0302 clinical medicine
MESH: Structure-Activity Relationship
MESH: Ligands
Humans
5-HT5A receptor
Receptors, Lipoxin
Receptor
Molecular Biology
Glucagon-like peptide 1 receptor
030304 developmental biology
G protein-coupled receptor
chemistry.chemical_classification
Inflammation
0303 health sciences
MESH: Humans
Tetrapeptide
MESH: N-Formylmethionine Leucyl-Phenylalanine
MESH: Neutrophil Activation
[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM]
Neutrophil
Cell Biology
Receptors, Formyl Peptide
N-Formylmethionine Leucyl-Phenylalanine
chemistry
Biochemistry
G-protein coupled receptor
Relaxin/insulin-like family peptide receptor 2
030215 immunology
Subjects
Details
- Language :
- English
- ISSN :
- 01674889
- Database :
- OpenAIRE
- Journal :
- Biochimica et Biophysica Acta-Molecular Cell Research, Biochimica et Biophysica Acta-Molecular Cell Research, Elsevier, 2015, 1853 (1), pp.192-200. ⟨10.1016/j.bbamcr.2014.10.021⟩
- Accession number :
- edsair.doi.dedup.....bafbec74e8d4613adbfd39149a34abd5