Switchable Membrane Remodeling and Antifungal Defense by Metamorphic Chemokine XCL1. ACS Infect Dis 2020 May 08;6(5):1204-1213
Date
04/04/2020Pubmed ID
32243126Pubmed Central ID
PMC7258946DOI
10.1021/acsinfecdis.0c00011Scopus ID
2-s2.0-85084720920 (requires institutional sign-in at Scopus site) 13 CitationsAbstract
Antimicrobial peptides (AMPs) are a class of molecules which generally kill pathogens via preferential cell membrane disruption. Chemokines are a family of signaling proteins that direct immune cell migration and share a conserved α-β tertiary structure. Recently, it was found that a subset of chemokines can also function as AMPs, including CCL20, CXCL4, and XCL1. It is therefore surprising that machine learning based analysis predicts that CCL20 and CXCL4's α-helices are membrane disruptive, while XCL1's helix is not. XCL1, however, is the only chemokine known to be a metamorphic protein which can interconvert reversibly between two distinct native structures (a β-sheet dimer and the α-β chemokine structure). Here, we investigate XCL1's antimicrobial mechanism of action with a focus on the role of metamorphic folding. We demonstrate that XCL1 is a molecular "Swiss army knife" that can refold into different structures for distinct context-dependent functions: whereas the α-β chemokine structure controls cell migration by binding to G-Protein Coupled Receptors (GPCRs), we find using small angle X-ray scattering (SAXS) that only the β-sheet and unfolded XCL1 structures can induce negative Gaussian curvature (NGC) in membranes, the type of curvature topologically required for membrane permeation. Moreover, the membrane remodeling activity of XCL1's β-sheet structure is strongly dependent on membrane composition: XCL1 selectively remodels bacterial model membranes but not mammalian model membranes. Interestingly, XCL1 also permeates fungal model membranes and exhibits anti-Candida activity in vitro, in contrast to the usual mode of antifungal defense which requires Th17 mediated cell-based responses. These observations suggest that metamorphic XCL1 is capable of a versatile multimodal form of antimicrobial defense.
Author List
Dishman AF, Lee MW, de Anda J, Lee EY, He J, Huppler AR, Wong GCL, Volkman BFAuthors
Anna Huppler MD Associate Professor in the Pediatrics department at Medical College of WisconsinBrian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
CandidaCell Membrane
Chemokines, C
Pore Forming Cytotoxic Proteins
Protein Folding
Protein Structure, Secondary
Scattering, Small Angle
X-Ray Diffraction
