Specific Histidine Residues Confer Histatin Peptides with Copper-Dependent Activity against Candida albicans
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The histidine-rich salivary peptides of the histatin family are known to bind copper (Cu) and other metal ions in vitro; however, the details of these interactions are poorly understood, and their implications for in vivo antifungal activity have not been established. Here, we show that the availability of Cu during exposure of Candida albicans to histatin-5 (Hist-5) modulates its antifungal activity. Antifungal susceptibility testing revealed that co-treatment of Hist-5 with Cu improved the EC50 from ∼5 to ∼1 μM, whereas co-treatment with a high-affinity Cu-specific chelator abrogated antifungal activity. Spectrophotometric titrations revealed two previously unrecognized Cu(I)-binding sites with apparent Kd values at pH 7.4, ∼20 nM, and confirmed a high-affinity Cu(II)-binding site at the Hist-5 N-terminus with an apparent Kd of ∼8 pM. Evaluation of a series of His-to-Ala full-length and truncated Hist-5 peptides identified adjacent His residues (bis-His) as critical anchors for Cu(I) binding, with the presence of a third ligand revealed by X-ray absorption spectroscopy. On their own, the truncated peptides were ineffective at inhibiting the growth of C. albicans, but treatment with supplemental Cu resulted in EC50 values down to ∼5 μM, approaching that of full-length Hist-5. The efficacy of the peptides depended on an intact bis-His site and correlated with Cu(I) affinity. Together, these results establish new structure–function relationships linking specific histidine residues with Cu binding affinity and antifungal activity and provide further evidence of the involvement of metals in modulating the biological activity of these antifungal peptides.
Published Version (Please cite this version)10.1021/acs.biochem.7b00348
Publication InfoConklin, Steven E; Bridgman, Emma C; Su, Qiang; Riggs-Gelasco, Pamela; Haas, Kathryn L; & Franz, Katherine J (2017). Specific Histidine Residues Confer Histatin Peptides with Copper-Dependent Activity against Candida albicans. Biochemistry. 10.1021/acs.biochem.7b00348. Retrieved from https://hdl.handle.net/10161/15179.
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Steven E. Conklin is originally from Guaynabo, Puerto Rico and graduated from the University of Puerto Rico – Río Piedras Campus in 2013 with a B.S. in Chemistry. Currently, he is a Chemistry Ph.D. candidate working in Katherine J. Franz’s laboratory, which focuses on bioinorganic chemistry.
Member of the Duke Cancer Institute
Research in the Franz group is involved in elucidating the structural and functional consequences of metal ion coordination in biological systems. We are particularly interested in understanding the coordination chemistry utilized by biology to manage essential yet toxic species like copper and iron. Understanding these principles further guides our development of new chemical tools to manipulate biological metal ion location, speciation, and reactivity for potential therapeutic benefit. We use
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