Copper regulates the interactions of antimicrobial piscidin peptides from fish mast cells with formyl peptide receptors and heparin

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Authors
Kim, So Young
Zhang, Fuming
Gong, Wanghua
Chen, Keqiang
Xia, Kai
Liu, Fei
Gross, Richard
Wang, Ji Ming
Linhardt, Robert J.
Cotten, Myriam L.
Issue Date
2018-10-05
Type
Article
Language
ENG
Keywords
Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
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Abstract
Phagocytic cells in fish secrete antimicrobial peptides (AMPs) such as piscidins, glycosaminoglycans such as heparin, and copper ions as first-line immune defenses. Recently, we established that Cu2+ coordination by piscidins 1 (P1) and 3 (P3) enhances their antibacterial activity against membranes and DNA. Interestingly, we noted that physicochemical similarities exist between both piscidins and other AMPs that interact with heparin and induce immune-cell chemotaxis through formyl peptide receptors (FPRs) involved in innate immunity. Thus, we postulated that P1 and P3 interact with heparin and FPRs but that these interactions distinctively depend on Cu2+ Here, we investigate the interactome potentiated by piscidins, heparin, FPR, and Cu2+ Utilizing FPR-transfected cells and neutrophils, we demonstrate that both piscidins exclusively use FPR1 and FPR2 to induce chemotaxis and that Cu2+ reduces their chemotaxis induction. P1 is more effective at activating FPR1 than P3 and other known AMP ligands. Furthermore, the expression of Fpr2 on the surface of neutrophils is down-regulated by both peptides. Copper conjugation of the peptides does not further increase down-regulation, suggesting that the conformational changes induced by the metal translate into reduced FPR efficacy without altering the binding affinity. Using surface plasmon resonance, we show that piscidin-heparin interactions are Cu2+-dependent and reduced at the acidic pH of phagosomes. Although heparin decreases the antimicrobial activity of P3-Cu2+, it does not affect bacterial killing by P1-Cu2+ Copper's effects on modulating the micromolar-range interactions of both piscidins with FPR and heparin suggest that the interactome of these distinct immune agents plays an important role in innate immunity. The interactions between diverse host-defense molecules uncovered here may help inform the design of novel therapeutics to treat immune-related diseases.
Description
Journal of Biological Chemistry, 293, 15381–15396
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Full Citation
Copper regulates the interactions of antimicrobial piscidin peptides from fish mast cells with formyl peptide receptors and heparin, S. Y. Kim, F. Zhang, W. Gong, K. Chen, K. Xia, F. Liu, R.A. Gross, J. M. Wang, R.J. Linhardt, M. L. Cotton, Journal of Biological Chemistry, 293, 15381–15396, 2018.
Publisher
Elsevier
Journal
Volume
Issue
PubMed ID
DOI
ISSN
1083351X
219258
EISSN