Zinc and copper bind to unique sites of histatin 5

Grogan, James; McKnight, C. James; Troxler, Robert F.; Oppenheim, Frank G.

doi:10.1016/s0014-5793(01)02157-3

Cited by 74 publications

(79 citation statements)

References 27 publications

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“…131,132 There is also evidence that histatin 1 and to a lesser extent histatin 3 and 5 are incorporated into the enamel pellicle by crosslink reactions catalysed by oral transglutaminase. 133 The first three residues (DSH) of histatins 3 and 5 represent the ATCUN motif, which complexes Cu 2+ and Ni 2+ ions (Grogan et al 2001). 134 Furthermore, two Zn 2+ -binding motifs (HEXXH) are present in histatin 1, and one such motif is present in histatins 3 and 5.…”

Section: Histatins: Candidacidal and Wound-closure Stimulating Amps Imentioning

confidence: 99%

“…133 The first three residues (DSH) of histatins 3 and 5 represent the ATCUN motif, which complexes Cu 2+ and Ni 2+ ions (Grogan et al 2001). 134 Furthermore, two Zn 2+ -binding motifs (HEXXH) are present in histatin 1, and one such motif is present in histatins 3 and 5. Complexation of metal ions may eliminate cofactors for enzymes and trace elements for microbial growth.…”

Section: Histatins: Candidacidal and Wound-closure Stimulating Amps Imentioning

confidence: 99%

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Antimicrobial peptides: The ancient arm of the human immune system

Wiesner¹,

Vilcinskas²

2010

Virulence

618

559

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The production of peptides and small proteins with microbicidal activity collectively called antimicrobial peptides (AMPs) is commonly considered to be a primitive mechanism of immunity and has been extensively studied in insects and other non-vertebrate organisms. In addition, a variety of AMPs present in amphibian skin secretion has been well characterised. There is now increasing evidence that AMPs play a crucial role in human immunity as well. Virtually all human tissues and cells typically exposed to microbes are able to produce AMPs. Important AMPs belonging to two structurally distinct classes, known as the defensins and the cathelicidins, are mainly produced by epithelial cells and neutrophils. AMPs significantly contributing to the chemical skin barrier are represented by dermcidin, psoriasin and RNase 7. The antimicrobial activity of saliva largely depends on histidine-rich AMPs known as histatins. Many more, in part less well-known AMPs and AMP-like proteins exist that exhibit various additional functions, apart from their antimicrobial properties. Among them, the neutrophil granule proteins azurocidin and cathepsin G are members of a family of serine-protease homologues called serprocidins and play a role in the regulation of the immune response and degradation of extracellular matrix proteins respectively. As another AMP-like protein of the neutrophil granule content, bactericidal/permeability increasing protein (BPI) is both able to permeabilise bacterial membranes and to function as an opsonin. The whey acidic protein (WAP) domain containing class of AMPs, including secretory leukocyte protease inhibitor (SLPI), elafin and trappin-2, is equally important in inhibition of neutrophil serine proteases and killing of microbes. Certain CC or CXC chemokines are known to possess antimicrobial properties and therefore are called kinocidins. Several kinocidins, including thrombocidin-1 and -2, are contained in the ?-granules of platelets. A cytoplasmic AMP described as ubiquicidin turned out to be identical with the strongly basic ribosomal protein S30. Proteolytic cleavage of the histone protein H2A in the stomach gives rise to an AMP initially described as buforin I. Adrenomedullin is a hormone-like AMP exhibiting vasodilatory and hypotensive effects. Lysozyme is mainly known for its cell wall degrading activity, but is also capable of non-enzymatic killing of bacteria. An iron-binding protein present in milk and other secretions named lactoferrin was shown to possess antimicrobial and antiviral activity and has been implicated in protection against cancer. Clinical studies on the treatment of infectious diseases have been performed with artificial peptides derived from human lactoferrin, histatins and BPI in addition to porcine protegrins, frog magains and bovine indolicidin. Omiganan, representing an indolicidin derivative, has been demonstrated to be effective in the treatment of acne and catheter-related local infections and is currently considered to be the most promising AMP-based drug candidate

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Section: Histatins: Candidacidal and Wound-closure Stimulating Amps Imentioning

confidence: 99%

Section: Histatins: Candidacidal and Wound-closure Stimulating Amps Imentioning

confidence: 99%

Antimicrobial peptides: The ancient arm of the human immune system

Wiesner¹,

Vilcinskas²

2010

Virulence

618

559

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“…Hst 5 binds Zn and Cu (71) and possesses definitive metal binding motifs (Fig. 1) for Cu and Ni (ACTUN motif, encompassing the first 3 N-terminal amino acids, Asp-SerHis) as well as for Zn (HEXXH motif at the C terminus [72,73]). Multiple strong binding sites within the binding motif are believed to occur for Cu, while Zn has only one strong putative metal binding site (74).…”

Section: Hst 5 Metal Binding Abilities As a Potential Candidacidal Mementioning

confidence: 99%

How Does It Kill?: Understanding the Candidacidal Mechanism of Salivary Histatin 5

2014

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Histatins are salivary cationic peptides that provide the first line of defense against oral candidiasis caused by Candida albicans. This minireview presents a critical evaluation of our knowledge of the candidacidal mechanism of histatin 5 (Hst 5). Hst 5 is the most potent among all histatin family members with regard to its antifungal activity. The mode of action of Hst 5 has been a subject of intense debate. Unlike other classical host innate immune proteins, pore formation or membrane lysis by Hst 5 has largely been disproven, and it is now known that all targets of Hst 5 are intracellular. Hst 5 binds C. albicans cell wall proteins (Ssa1/2) and glycans and is taken up by the cells through fungal polyamine transporters in an energy-dependent manner. Once inside the fungal cells, Hst 5 may affect mitochondrial functions and cause oxidative stress; however, the ultimate cause of cell death is by volume dysregulation and ion imbalance triggered by osmotic stress. Besides these diverse targets, a novel mechanism based on the metal binding abilities of Hst 5 is discussed. Finally, translational approaches for Hst 5, based on peptide design and synergy with other known drugs, are considered a step forward for bench-to-bed application of Hst 5.

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“…In fact Melino et al [20] have demonstrated that the peptide in the presence of zinc ions is able to aggregate and fuse negatively charged unilamellar vesicles and subsequently it has been reported that histatin-5 binds copper and nickel through its N-terminal ATCUN motif [21].…”

mentioning

confidence: 99%

Respiratory inhibition of isolated mammalian mitochondria by salivary antifungal peptide histatin-5

Petruzzelli

Clementi²,

Marini

et al. 2003

Biochemical and Biophysical Research Communications

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Histatin-5 is a peptide secreted in the human saliva, which possesses powerful antifungal activity. Previous studies have shown that this peptide exerts its candidacidal activity, through the inhibition of both mitochondrial respiration and the formation of reactive oxygen species. The purpose of the present study was to investigate the biological consequences of histatin-5 action on mammalian mitochondria to verify if the toxic mechanism exerted on mitochondria from Candida albicans is an exclusive for fungal cells. Moreover, hypothesising that the damage exerted on mitochondria may induce programmed cellular death pathways, we evaluated two main markers of apoptosis: the mitochondrial membrane potential (DW) and the release of cytochrome c. The results obtained show that exposure of isolated mammalian mitochondria to histatin-5 determines: (i) a large inhibition of the respiratory chain at the level of complex I, (ii) a slight decrease in the mitochondrial membrane potential, and (iii) no release of cytochrome c.

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Zinc and copper bind to unique sites of histatin 5

Cited by 74 publications

References 27 publications

Antimicrobial peptides: The ancient arm of the human immune system

Antimicrobial peptides: The ancient arm of the human immune system

How Does It Kill?: Understanding the Candidacidal Mechanism of Salivary Histatin 5

Respiratory inhibition of isolated mammalian mitochondria by salivary antifungal peptide histatin-5

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