Histatins: Salivary peptides with copper(II)- and zinc(II)-binding motifs Original paper

What was studied?

This study explored the interaction of copper ions with histatin peptides, focusing on histatin-5 (Hist-5) and its ability to bind copper. The researchers specifically examined the copper-binding sites of Hist-5 and how these interactions contribute to its antimicrobial properties, particularly against Candida albicans. They investigated the role of the bis-histidine (bis-His) motif, which is believed to be critical for Cu(I) binding, as well as the potential for copper to modulate the peptide’s antifungal activity.

Who was studied?

The study was centered on Hist-5, a histidine-rich antimicrobial peptide found in human saliva. Hist-5 is known for its ability to combat fungal pathogens like Candida albicans, an opportunistic yeast that affects mucosal membranes. The research focused on the structural and functional properties of this peptide, particularly how it binds copper ions and how this influences its effectiveness against microbial infections.

Most important findings

The research found that Hist-5 binds copper through specific motifs, namely the amino-terminal copper/nickel-binding (ATCUN) motif and the bis-His motif. These motifs allow Hist-5 to exhibit copper-dependent antimicrobial activity. The ATCUN motif binds Cu(II) and Ni(II), while the bis-His site is specifically responsible for binding Cu(I), which plays a key role in the peptide’s antifungal activity. The study also revealed that the affinity of Hist-5 for Cu(I) is significantly enhanced by the presence of histidine residues in adjacent positions. Furthermore, the copper-bound Hist-5 exhibited a higher affinity for the pathogen Candida albicans, facilitating its internalization into fungal cells, where it interacts with mitochondria and generates reactive oxygen species (ROS), leading to fungal cell death. The research emphasized that the copper-binding properties of Hist-5 are crucial for its biological activity, as these interactions stabilize its structure and modulate its ability to kill fungal cells.

Key implications

These findings underscore the importance of metal ions, specifically copper, in the antimicrobial activity of salivary peptides like Hist-5. Understanding the metal-binding mechanisms of Hist-5 provides valuable insights into the development of novel therapeutic strategies based on metal-mediated peptide interactions. This study suggests that Hist-5 or similar peptides could be further optimized to enhance their antimicrobial effectiveness against fungal infections, especially those caused by Candida albicans. Additionally, the copper-binding motifs identified could be targeted in drug design to create peptides that mimic Hist-5’s functionality, offering a potential alternative to traditional antifungal treatments.