Bioinformatic analysis reveals new determinants of antigenic 14-3-3 proteins and a novel antifungal strategy

Abstract

The ubiquitously expressed 14-3-3 family of proteins is evolutionarily conserved from yeast to mammals. Their involvement in humoral and cellular immune responses is emerging through studies in drosophila and humans. In humans, a select group of 14-3-3 isoforms are antigenic; however the determinants of their antigenicity are not known. Here, we show that although mammalian 14-3-3 proteins are mostly conserved, subtle differences between their isoforms may give rise to their antigenicity. We observed syntenic relations among all the isoforms of 14-3-3 for mammals, but not with that of birds or amphibians. However, the parasitic 14-3-3 isoforms, which have known antigenic properties, show unique sequence, structure and evolution compared to the human 14-3-3. Moreover we report, for the first time the existence of a bacterial 14-3-3 protein. Contrary to the parasitic isoforms, both bacterial and yeast 14-3-3 exhibited significant homology with mammalian 14-3-3 in protein sequence as well as structure. Furthermore, a human 14-3-3 inhibitor caused significant killing of Candida albicans, which could be due to the inhibition of the structurally similar yeast homologue of 14-3-3, BMH, which is essential for its life cycle. Overall, our bioinformatic analysis combined with the demonstration of a novel antifungal role of a peptide inhibitor of human 14-3-3 indicates that the sequences and structural similarities between the mammalian, bacterial and fungal proteins are likely determinants of the antigenic nature of these proteins. Further, we propose that molecular mimicry triggered by microbial infections with either yeast or bacteria may contribute to the antigenic role of human 14-3-3.