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Innate Immun. 2016 Apr;22(3):218-29. doi: 10.1177/1753425916631404. Epub 2016 Feb 15.

Carbamylated LL-37 as a modulator of the immune response.

Author information

1
Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway.
2
Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland.
3
Interdisciplinary Nanoscience Center at the Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
4
Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
5
Periodontal Research Group MRC Centre for Immune Regulation, University of Birmingham, Birmingham, UK.
6
Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland Department of Oral Immunology and Infectious Diseases, University of Louisville School of Dentistry, Louisville, KY, USA.
7
Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland piotr.mydel@uib.no.

Abstract

Carbamylation of lysine residues and protein N-termini is an ubiquitous, non-enzymatic post-translational modification. Carbamylation at sites of inflammation is due to cyanate formation during the neutrophil oxidative burst and may target lysine residues within the antimicrobial peptide LL-37. The bactericidal and immunomodulatory properties of LL-37 depend on its secondary structure and cationic nature, which are conferred by arginine and lysine residues. Therefore, carbamylation may affect the biological functions of LL-37. The present study examined the kinetics and pattern of LL-37 carbamylation to investigate how this modification affects the bactericidal, cytotoxic and immunomodulatory function of the peptide. The results indicated that LL-37 undergoes rapid modification in the presence of physiological concentrations of cyanate, yielding a spectrum of diverse carbamylated peptides. Mass spectrometry analyses revealed that theN-terminal amino group of Leu-1 was highly reactive and was modified almost instantly by cyanate to generate the predominant form of the modified peptide, named LL-37(C1) This was followed by the sequential carbamylation of Lys-8, Lys-12, and Lys-15 to yield LL-37(C8), and Lys-15 to yield LL-37(C12,15) Carbamylation had profound and diverse effects on the structure and biological properties of LL-37. In some cases, anti-inflammatory LL-37 was rapidly converted to pro-inflammatory LL-37.

KEYWORDS:

Carbamylation; LL-37; immunomodulation

PMID:
26878866
PMCID:
PMC5143673
DOI:
10.1177/1753425916631404
[Indexed for MEDLINE]
Free PMC Article

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