Abstract
Candida species cause serious infections requiring prolonged and sometimes toxic therapy. Antimicrobial proteins, such as chemokines, hold great interest as potential additions to the small number of available antifungal drugs. Metamorphic proteins reversibly switch between multiple different folded structures. XCL1 is a metamorphic, antimicrobial chemokine that interconverts between the conserved chemokine fold (an α–β monomer) and an alternate fold (an all-β dimer). Previous work has shown that human XCL1 kills C. albicans but has not assessed whether one or both XCL1 folds perform this activity. Here, we use structurally locked engineered XCL1 variants and Candida killing assays, adenylate kinase release assays, and propidium iodide uptake assays to demonstrate that both XCL1 folds kill Candida, but they do so via different mechanisms. Our results suggest that the alternate fold kills via membrane disruption, consistent with previous work, and the chemokine fold does not. XCL1 fold-switching thus provides a mechanism to regulate the XCL1 mode of antifungal killing, which could protect surrounding tissue from damage associated with fungal membrane disruption and could allow XCL1 to overcome candidal resistance by switching folds. This work provides inspiration for the future design of switchable, multifunctional antifungal therapeutics.
Highlights
Candida albicans and other fungal pathogens cause severe and costly infections in children and adults [1,2,3]
High incidence of drug toxicity and the emergence of resistance limit the utility of available antifungal drug classes [4,5]
A recent study found that XCL1 and CCL28 are expressed highly in uterine tissue, perhaps suggesting that the antimicrobial properties of these chemokines contribute to the protection of the developing fetus from microbial pathogens [27]
Summary
Candida albicans and other fungal pathogens cause severe and costly infections in children and adults [1,2,3]. Interest in the biological relevance of metamorphic protein folding is growing, and efforts to understand and harness protein metamorphosis for therapeutic benefit are beginning to mount [10,11,12] One such metamorphic protein is the antimicrobial human chemokine XCL1. The XCL1 Chemokine Fold, Alternate Fold, and Unfolded State Kill C. albicans. CTCh3e (XloCcLke1dCchheemmookkiinnee Ffoolldd), aAnldteCrnCa5t(eloFcokledd, aanltderUnantefoflodledd) S(FtiagtuerKe i1l)l.CA.dadlbitiicoannaslly, an Engineered XCL1 variants have been designed to lock XCL1 into the chemokine fold [16] and the alternate fold [17] by adding a new disulfide bond. Suggests that the XCL1 alternate fold kills via membrane disruption, but the XCL1 chemokine fold does not, in concurrence with the AKA data presented in the previous section. SSiiggnniifificcaanntt ddiiffffeerreenncceessbbeettwweeeennXXCCLL11aannddCCCC33iinnddiiccaatteeddwwiitthh**ffoorrpp
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