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Specific Histidine Residues Confer Histatin Peptides with Copper-Dependent Activity against Candida albicans

Publication ,  Journal Article
Conklin, SE; Bridgman, EC; Su, Q; Riggs-Gelasco, P; Franz, KJ
Published in: Biochemistry
August 1, 2017

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.

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Published In

Biochemistry

DOI

ISSN

0006-2960

Publication Date

August 1, 2017

Publisher

American Chemical Society

Related Subject Headings

  • Humans
  • Histatins
  • Copper
  • Candida albicans
  • Biochemistry & Molecular Biology
  • Antifungal Agents
  • 3404 Medicinal and biomolecular chemistry
  • 3205 Medical biochemistry and metabolomics
  • 3101 Biochemistry and cell biology
  • 1101 Medical Biochemistry and Metabolomics
 

Citation

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Conklin, S. E., Bridgman, E. C., Su, Q., Riggs-Gelasco, P., & Franz, K. J. (2017). Specific Histidine Residues Confer Histatin Peptides with Copper-Dependent Activity against Candida albicans. Biochemistry. https://doi.org/10.1021/acs.biochem.7b00348
Conklin, S. E., E. C. Bridgman, Q. Su, P. Riggs-Gelasco, and K. J. Franz. “Specific Histidine Residues Confer Histatin Peptides with Copper-Dependent Activity against Candida albicans.” Biochemistry, August 1, 2017. https://doi.org/10.1021/acs.biochem.7b00348.
Conklin SE, Bridgman EC, Su Q, Riggs-Gelasco P, Franz KJ. Specific Histidine Residues Confer Histatin Peptides with Copper-Dependent Activity against Candida albicans. Biochemistry. 2017 Aug 1;
Conklin, S. E., et al. “Specific Histidine Residues Confer Histatin Peptides with Copper-Dependent Activity against Candida albicans.” Biochemistry, American Chemical Society, Aug. 2017. Manual, doi:10.1021/acs.biochem.7b00348.
Conklin SE, Bridgman EC, Su Q, Riggs-Gelasco P, Franz KJ. Specific Histidine Residues Confer Histatin Peptides with Copper-Dependent Activity against Candida albicans. Biochemistry. American Chemical Society; 2017 Aug 1;
Journal cover image

Published In

Biochemistry

DOI

ISSN

0006-2960

Publication Date

August 1, 2017

Publisher

American Chemical Society

Related Subject Headings

  • Humans
  • Histatins
  • Copper
  • Candida albicans
  • Biochemistry & Molecular Biology
  • Antifungal Agents
  • 3404 Medicinal and biomolecular chemistry
  • 3205 Medical biochemistry and metabolomics
  • 3101 Biochemistry and cell biology
  • 1101 Medical Biochemistry and Metabolomics