Abstract
BackgroundHistatins are histidine rich polypeptides produced in the parotid and submandibular gland and secreted into the saliva. Histatin-3 and −5 are the most important polycationic histatins. They possess antimicrobial activity against fungi such as Candida albicans. Histatin-5 has a higher antifungal activity than histatin-3 while histatin-3 is mostly involved in wound healing in the oral cavity. We found that these histatins, like other polycationic peptides and proteins, such as LL-37, lysozyme and histones, interact with extracellular actin.ResultsHistatin-3 and −5 polymerize globular actin (G-actin) to filamentous actin (F-actin) and bundle F-actin filaments. Both actin polymerization and bundling by histatins is pH sensitive due to the high histidine content of histatins. In spite of the equal number of net positive charges and histidine residues in histatin-3 and −5, less histatin-3 is needed than histatin-5 for polymerization and bundling of actin. The efficiency of actin polymerization and bundling by histatins greatly increases with decreasing pH. Histatin-3 and −5 induced actin bundles are dissociated by 100 and 50 mM NaCl, respectively. The relatively low NaCl concentration required to dissociate histatin-induced bundles implies that the actin-histatin filaments bind to each other mainly by electrostatic forces. The binding of histatin-3 to F-actin is stronger than that of histatin-5 showing that hydrophobic forces have also some role in histatin-3- actin interaction. Histatins affect the fluorescence of probes attached to the D-loop of G-actin indicating histatin induced changes in actin structure. Transglutaminase cross-links histatins to actin. Competition and limited proteolysis experiments indicate that the main histatin cross-linking site on actin is glutamine-49 on the D-loop of actin.ConclusionsBoth histatin-3 and −5 interacts with actin, however, histatin 3 binds stronger to actin and affects actin structure at lower concentration than histatin-5 due to the extra 8 amino acid sequence at the C-terminus of histatin-3. Extracellular actin might regulate histatin activity in the oral cavity, which should be the subject of further investigation.
Highlights
Histatins are histidine rich polypeptides produced in the parotid and submandibular gland and secreted into the saliva
Histatin-3 fully polymerized 4 μM globular actin (G-actin) at 12 μM concentration (Fig. 1a and c) but more than 28 μM histatin-5 was needed to achieve a similar degree of polymerization (Fig. 1b)
We found that phalloidin reduces greatly the extent of filamentous actin (F-actin) cross-linking with Flhistatin-3, Fl-histatin-5 and Fl-LL-37 (Fig. 6b), which supports the above hypothesis
Summary
Histatins are histidine rich polypeptides produced in the parotid and submandibular gland and secreted into the saliva. Histatin-5 has a higher antifungal activity than histatin-3 while histatin-3 is mostly involved in wound healing in the oral cavity. We found that these histatins, like other polycationic peptides and proteins, such as LL-37, lysozyme and histones, interact with extracellular actin. Histatins are histidine rich cationic peptides synthetized in the parotid and submandibular salivary glands and released into the saliva. The sequence of the motif in histatins is Asp-Ser-His. The copper complex of the motif generates reactive oxygen species, which has an important role in the antifungal activity of histatins [4]. Histatins have a positive role in wound healing in the oral cavity [5]
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