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Lymphotactin/XCL1, the defining member of the C class of chemokines, undergoes a conformational change that involves the complete restructuring of all stabilizing interactions. Other chemokines are restricted to a single conformation by a pair of conserved disulfide crosslinks, one of which is absent in lymphotactin. This structural interconversion is entirely reversible, and the two-state equilibrium is sensitive to changes in temperature and ionic strength. One species adopts the conserved chemokine fold as a monomer and functions as an agonist for XCR1, the specific G-protein-coupled receptor for lymphotactin. Rearrangement to the other conformation produces a novel four-stranded sheet that dimerizes to form a beta sandwich with high affinity for cell-surface glycosaminoglycans. We developed methods for resolving the two species and investigated the dynamics of human lymphotactin structural interconversion with NMR spectroscopy, heparin affinity chromatography, and time-resolved fluorescence on the wild-type protein and a panel of amino acid-substituted lymphotactin variants. Our results show that the lymphotactin structural rearrangement occurs at a rate of approximately 1/s and that mutation of residues required for glycosaminoglycan binding shifts the conformational equilibrium toward the chemokine-like fold. We speculate that charge repulsion between arginines 23 and 43 destabilizes the chemokine fold and promotes conversion to the novel lymphotactin dimer, whereas binding of chloride or another anion stabilizes the chemokine fold by neutralizing the repulsive effect.
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http://dx.doi.org/10.1016/S0076-6879(09)05403-2 | DOI Listing |
Protein J
June 2023
Department of Chemical Science and Technology, University of Rome "Tor Vergata", Via Della Ricerca Scientifica 1, 00185, Rome, Italy.
Metamorphic, or fold-switching, proteins feature different folds that are physiologically relevant. The human chemokine XCL1 (or Lymphotactin) is a metamorphic protein that features two native states, an [Formula: see text] and an all[Formula: see text] fold, which have similar stability at physiological condition. Here, extended molecular dynamics (MD) simulations, principal component analysis of atomic fluctuations and thermodynamic modeling based on both the configurational volume and free energy landscape, are used to obtain a detailed characterization of the conformational thermodynamics of human Lymphotactin and of one of its ancestors (as was previously obtained by genetic reconstruction).
View Article and Find Full Text PDFJ Phys Chem B
July 2020
Department of Chemistry & Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States.
Lymphotactin (Ltn) exists under physiological conditions in an equilibrium between two interconverting structures with distinct biological functions. Using replica-exchange-with-tunneling, we study the conversion between the 2-folds. Unlike previously proposed, we find that the fold switching does not require unfolding of lymphotactin but proceeds through a series of intermediates that remain partially structured.
View Article and Find Full Text PDFFront Immunol
September 2019
Division of Chemotherapy, Kindai University Faculty of Pharmacy, Osaka, Japan.
The chemokine receptor XCR1 is known to be selectively expressed by cross-presenting dendritic cells (DCs), while its ligand XCL1/lymphotactin is mainly produced by activated CD8 T cells and natural killer cells. Recent studies have shown that XCL1-antigen fusion proteins efficiently induce CD8 T cell responses by preferentially delivering antigens to XCR1 DCs. However, XCL1 was found to be a poor adjuvant for induction of CD8 T cell responses.
View Article and Find Full Text PDFChem Commun (Camb)
January 2016
School of Chemistry, University of Edinburgh, West Mains Road, EH8 3JJ, Edinburg, UK.
Transmission electron microscopy, mass spectrometry, and drift tube ion mobility-mass spectrometry are used to study the assemblies formed by the metamorphic chemokine lymphotactin in the presence of a model pentameric glycosaminoglycan, fondaparinux. This combination of techniques delineates significant differences in the complexes observed for two forms of the full length protein as well as a truncated form, without the intrinsically disordered C-terminal tail, over a length scale from few nm to μm assemblies.
View Article and Find Full Text PDFACS Chem Biol
November 2015
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States.
Unlike other chemokines, XCL1 undergoes a distinct metamorphic interconversion between a canonical monomeric chemokine fold and a unique β-sandwich dimer. The monomeric conformation binds and activates the receptor XCR1, whereas the dimer binds extracellular matrix glycosaminoglycans and has been associated with anti-human immunodeficiency virus (HIV) activity. Functional studies of WT-XCL1 are complex, as both conformations are populated in solution.
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