Switchable Membrane Remodeling and Antifungal Defense by Metamorphic Chemokine XCL1

• DOI: 10.1021/acsinfecdis.0c00011
• Publication Date: 2020-04-03T18:08:56Z
• Authors: Acacia F. Dishman; Michelle W. Lee; Jaime de Anda; Ernest Y. Lee; Jie He; Anna R. Huppler; Gerard C. L. Wong; Brian F. Volkman
• Keywords: metamorphic proteins; Pore Forming Cytotoxic Proteins; 0301 basic medicine; 570; Protein Folding; XCL1; Cell Membrane; 610; chemokines; Protein Structure, Secondary; Chemokines, C; 03 medical and health sciences; X-Ray Diffraction; small-angle X-ray scattering; Scattering, Small Angle; antimicrobial; antifungal; Candida

Antimicrobial peptides (AMPs) are a class of molecules which generally kill pathogens via preferential cell membrane disruption. Chemokines family signaling proteins that direct immune migration and share conserved α–β tertiary structure. Recently, it was found subset chemokines can also function as AMPs, including CCL20, CXCL4, XCL1. It is therefore surprising machine learning based analysis predicts CCL20 CXCL4's α-helices disruptive, while XCL1's helix not. XCL1, however, the only chemokine known to be metamorphic protein interconvert reversibly between two distinct native structures (a β-sheet dimer structure). Here, we investigate antimicrobial mechanism action with focus on role folding. We demonstrate XCL1 molecular "Swiss army knife" refold into different for context-dependent functions: whereas structure controls by binding G-Protein Coupled Receptors (GPCRs), find using small angle X-ray scattering (SAXS) unfolded induce negative Gaussian curvature (NGC) in membranes, type topologically required permeation. Moreover, remodeling activity strongly dependent composition: selectively remodels bacterial model membranes but not mammalian membranes. Interestingly, permeates fungal exhibits anti-Candida vitro, contrast usual mode antifungal defense requires Th17 mediated cell-based responses. These observations suggest capable versatile multimodal form defense.