Interactions of histatin 5 and histatin 5-derived peptides with liposome membranes: surface effects, translocation and permeabilization

Abstract

A number of cationic antimicrobial peptides, among which are histatin 5 and the derived peptides dhvar4 and dhvar5, enter their target cells and interact with internal organelles. There still are questions about the mechanisms by which antimicrobial peptides translocate across the membrane. We used a liposome model to study membrane binding, translocation and membrane-perturbing capacities of histatin 5, dhvar4 and dhvar5. Despite the differences in amphipathic characters of these peptides, they bound equally well to liposomes, whereas their membrane activities differed remarkably: dhvar4 translocated at the fastest rate, followed by dhvar5, whereas the histatin 5 translocation rate was much lower. The same pattern was seen for the extent of calcein release: highest with dhvar4, less with dhvar5 and almost none with histatin 5. The translocation and disruptive actions of dhvar5 did not seem to be coupled, because translocation occurred on a much longer timescale than calcein release, which ended within a few minutes. We conclude that peptide translocation can occur through peptide-phospholipid interactions, and that this is a possible mechanism by which antimicrobial peptides enter cells. However, the translocation rate was much lower in this model membrane system than that seen in yeast cells. Thus it is likely that, at least for some peptides, additional features promoting the translocation across biological membranes are involved as well.

Escherichia coli Cell Surface Perturbation and Disruption Induced by Antimicrobial Peptides BP100 and pepR

“…below MIC) can be attributed, at least initially, to electrostatics. Several studies investigating the interaction of cationic AMPs with model bacterial membranes have shown that an overcompensation in zeta potential at high peptide concentrations is associated with membrane insertion via hydrophobic interactions (22)(23)(24). A similar trend was also reported for the interaction of the cationic peptide rBPI 21 with LPS aggregates (24).…”

A Membrane-Destabilizing Peptide in Capsid Protein L2 Is Required for Egress of Papillomavirus Genomes from Endosomes

“…In a search for possible membrane-disturbing domains within the PV L2 protein, we observed similarity of a carboxyl-terminal L2 peptide with the synthetic peptide dhvar5 (LLLFLLKKRKKRKY) (Fig. 2A), which was recently shown to destabilize and depolarize membranes of bacteria and fungi, resulting in strong microbicidal and fungicidal activities (12). Peptide dhvar5 is a derivative of histatin 5, a human antimicrobial and antifungal peptide found in human saliva.…”

“…This, in turn, would allow insight into the precise mechanism of peptide action. Using liposomes, it was recently shown for dhvar5 that negatively charged phospholipids are required for the peptide to translocate across and permeabilize membranes (12).…”

Histatin 5 Initiates Osmotic Stress Response in Candida albicans via Activation of the Hog1 Mitogen-Activated Protein Kinase Pathway

“…Hst 5 is not a classical pore-or channel-forming peptide, since it has little disruptive activity in liposome model membranes (9) and cells treated with Hst 5 do not release dyes such as calcein (11). However, Hst 5 induces efflux of cellular ATP (20) and potassium and magnesium ions (42) and elevates cell permeability to small cationic dyes such as propidium iodide (40).…”