Carbamylated LL-37 as a modulator of the immune response. Issue 3 (April 2016)

• Record Type: Journal Article
• Authors: Koro, Catalin; Hellvard, Annelie; Delaleu, Nicolas; Binder, Veronika; Scavenius, Carsten; Bergum, Brith; Główczyk, Izabela; Roberts, Helen M; Chapple, Iain LC; Grant, Melissa M; Rapala-Kozik, Maria; Klaga, Kinga; Enghild, Jan J; Potempa, Jan; Mydel, Piotr
• Is Part Of: Innate immunity. Volume 22:Issue 3(2016:Apr.)
• Page Start: 218
• Page End: 229
• Publication Date: 2016-04
• Subjects: Carbamylation -- LL-37 -- immunomodulation; Natural immunity -- Periodicals; Endotoxins -- Periodicals; 616.07905
• DOI: 10.1177/1753425916631404
• Languages: English
• ISSNs: 1753-4259

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 the N -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.