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Originally published In Press as doi:10.1074/jbc.M008229200 on November 30, 2000

J. Biol. Chem., Vol. 276, Issue 8, 5643-5649, February 23, 2001
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Characterization of Histatin 5 with Respect to Amphipathicity, Hydrophobicity, and Effects on Cell and Mitochondrial Membrane Integrity Excludes a Candidacidal Mechanism of Pore Formation*

Eva J. Helmerhorst, Wim van't Hof, Pieter Breeuwer||, Enno C. I. Veerman, Tjakko Abee||, Robert F. TroxlerDagger , Arie V. Nieuw Amerongen, and Frank G. OppenheimDagger

From the Dagger  Department of Periodontology and Oral Biology, Boston University Goldman School of Dental Medicine, Boston, Massachusetts 02118, the  Department of Oral Biochemistry, Academic Center for Dentistry (ACTA), 1081 BT, Amsterdam, The Netherlands, and the || Department of Food Technology and Nutritional Sciences, Laboratory of Food Microbiology, 6703 HD, Wageningen, The Netherlands

Histatin 5 is a 24-residue peptide from human saliva with antifungal properties. We recently demonstrated that histatin 5 translocates across the yeast membrane and targets to the mitochondria, suggesting an unusual antifungal mechanism (Helmerhorst, E. J., Breeuwer, P., van`t Hof, W., Walgreen-Weterings, E., Oomen, L. C. J. M., Veerman, E. C. I., Nieuw Amerongen, A. V., and Abee, T. (1999) J. Biol. Chem. 274, 7286-7291). The present study used specifically designed synthetic analogs of histatin 5 to elucidate the role of peptide amphipathicity, hydrophobicity, and the propensity to adopt alpha -helical structures in relation to membrane permeabilization and fungicidal activity. Studies included circular dichroism measurements, evaluation of the effects on the cytoplasmic transmembrane potential and on the respiration of isolated mitochondria, and analysis of the peptide hydrophobicity/amphipathicity relationship (Eisenberg, D. (1984) Annu. Rev. Biochem. 53, 595-623). The 14-residue synthetic peptides used were dh-5, comprising the functional domain of histatin 5, and dhvar1 and dhvar4, both designed to maximize amphipathic characteristics. The results obtained show that the amphipathic analogs exhibited a high fungicidal activity, a high propensity to form an alpha -helix, dissipated the cytoplasmic transmembrane potential, and uncoupled the respiration of isolated mitochondria, similar to the pore-forming peptide PGLa (Peptide with N-terminal Glycine and C-terminal Leucine-amide). In contrast, histatin 5 and dh-5 showed fewer or none of these features. The difference in these functional characteristics between histatin 5 and dh-5 on the one hand and dhvar1, dhvar4, and PGLa on the other hand correlated well with their predicted affinity for membranes based on hydrophobicity/amphipathicity analysis. These data indicate that the salivary protein histatin 5 exerts its antifungal function through a mechanism other than pore formation.

* This project was supported in part by the Dutch Technology Foundation, and Unilever Research Grant. VTH 44.3302, and by National Institutes of Health Grants DE05672 and DE07652 (NIDCR).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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