Switchable Membrane Remodeling and Antifungal Defense by Metamorphic Chemokine XCL1
- 8 May 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in ACS Infectious Diseases
- Vol. 6 (5), 1204-1213
- https://doi.org/10.1021/acsinfecdis.0c00011
Abstract
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 alpha-beta 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 alpha-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 beta-sheet dimer and the alpha-beta 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 alpha-beta 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 beta-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 beta-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.Funding Information
- National Cancer Institute (F30 CA236182)
- National Institute of Dental and Craniofacial Research (K08 DE026189)
- National Institute of Allergy and Infectious Diseases (R01 AI052453, R01 AI058072, R01 AI120655)
- Division of Graduate Education (DGE-1650604)
- National Psoriasis Foundation
- Division of Materials Research (DMR 1808459)
- Children's Hospital of Wisconsin Research Institute
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