Structure‐dependent functional properties of human defensin 5

Abstract

The mucosal epithelium secretes a variety of antimicrobial peptides that act as part of the innate immune system to protect against invading microbes. Here, we describe the functional properties of human defensin (HD) 5, the major antimicrobial peptide produced by Paneth cells in the ileum, in relation to its structure. The antimicrobial activity of HD-5 against Escherichia coli proved to be independent of its structure, whereas the unstructured peptide showed greatly reduced antimicrobial activity against Staphylococcus aureus. We find that HD-5 binds to the cell membrane of intestinal epithelial cells and induced secretion of the chemokine interleukin (IL)-8 in a concentration-and structure-dependent fashion. Incubation of HD-5 in the presence of tumor necrosis factor alpha further increased IL-8 secretion synergistically, suggesting that HD-5 may act as a regulator of the intestinal inflammatory response. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.

Functional Determinants of Human Enteric α-Defensin HD5

“…3 shows the survival of E. coli or S. aureus against HD5 and analogues ranging in concentration from 0.195 to 50 M. Virtual lethal dose values are given in Table 2. As observed previously, S. aureus was more susceptible to HD5 than E. coli (14,65). Strikingly, L29A-HD5 showed essentially no bactericidal activity against S. aureus, even at the highest concentration tested (50 M), and showed reduced killing of E. coli.…”

Trp-26 Imparts Functional Versatility to Human α-Defensin HNP1

“…Some Structurally Conserved Elements, although Essential for Defensin Biosynthesis, Do Not Contribute to HNP1 FunctionEarlier structure-activity studies of ␣-defensins, including our own, typically focused on their conserved structural elements (23)(24)(25)(26)(27)(28), including an invariant Gly-17, a salt bridge between Arg-5 and Glu-13 (using HNP1 numbering), and disulfide bonding. Gly-17, part of an atypical ␤-bulge structure, is critical for ␣-defensin folding, whereas the salt bridge stabilizes ␣-defensins to prevent their in vivo degradation by proteases.…”

“…Prior mutational studies of ␣-defensins focused primarily on conserved elements such as disulfide bonding (23,24), an invariant Gly residue (25), a conserved salt bridge (26 -28), and the often abundant but less conserved Arg residues (29,30). However, the loss of many of those conserved structural elements in ␣-defensins is often functionally inconsequential in vitro.…”

Neisseria gonorrhoeae-Induced Human Defensins 5 and 6 Increase HIV Infectivity: Role in Enhanced Transmission

“…50 and data not shown for HD6). HD5 R9H, a known single nucleotide polymorphism, and HD5 R13H, an analog with Arg replaced by His, both contain intact disulfide bonds and both exhibited HIV-enhancing effects ( Fig.…”