@article{86963e6c587640618633c03e13380aa0,
title = "Cholesteryl esters stabilize human CD1c conformations",
abstract = "Cluster of differentiation 1c (CD1c)-dependent self-reactive T cells are abundant in human blood, but self-antigens presented by CD1c to the T-cell receptors of these cells are poorly understood. Here we present a crystal structure of CD1c determined at 2.4 {\AA} revealing an extended ligand binding potential of the antigen groove and a substantially different conformation compared with known CD1c structures. Computational simulations exploring different occupancy states of the groove reenacted these different CD1c conformations and suggested cholesteryl esters (CE) and acylated steryl glycosides (ASG) as new ligand classes for CD1c. Confirming this, we show that binding of CE and ASG to CD1c enables the binding of human CD1c self-reactive T-cell receptors. Hence, human CD1c adopts different conformations dependent on ligand occupancy of its groove, with CE and ASG stabilizing CD1c conformations that provide a footprint for binding of CD1c self-reactive T-cell receptors.",
keywords = "Antigen presentation, CD1, Cholesteryl ester, Lipid antigen, Tcell",
author = "Salah Mansour and Tocheva, {Anna S.} and Chris Cave-Ayland and Machelett, {Moritz M.} and Barbara Sander and Lissin, {Nikolai M.} and Molloy, {Peter E.} and Baird, {Mark S.} and Gunthard St{\"u}bs and Schr{\"o}der, {Nicolas W.J.} and Schumann, {Ralf R.} and J{\"o}rg Rademann and Postle, {Anthony D.} and Jakobsen, {Bent K.} and Marshall, {Ben G.} and Rajendra Gosain and Elkington, {Paul T.} and Tim Elliott and Skylaris, {Chris Kriton} and Essex, {Jonathan W.} and Ivo Tews and Gadola, {Stephan D.}",
note = "Funding Information: We thank the following for their invaluable support of this work: Stuart Findlow and Chris Holes at the Macromolecular Crystallisation Facility at the Centre for Biological Sciences, Pete Horton and Simon Coles at the Southampton Diffraction Centre for support, the staff at the Diamond Light Source for excellent user support, and Richard Jewell and Carolann McGuire (FACS facility, Faculty of Medicine, University of Southampton). Special thanks to Dr. David Branch Moody (Harvard Medical School) for donating CD1 group 1 restricted T-cell lines and clones (CD8-1, CD8-2, and LDN5), the chemical computing group for an MOE license, and the Emerald High Performance Computing facility. This work was supported by the Higher Education Funding Council for England (S.D.G. and S.M.), Biotechnology and Biological Sciences Research Council Grant BB/J017302/1 (to A.S.T.), Engineering and Physical Sciences Research Council Grant EP/G03690X/1 (to C.C.-A.), and the Wessex innovation grant fund (S.D.G. and S.M.). Publisher Copyright: {\textcopyright} 2016, National Academy of Sciences. All rights reserved.",
year = "2016",
month = mar,
day = "1",
doi = "10.1073/pnas.1519246113",
language = "English",
volume = "113",
pages = "E1266--E1275",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "9",
}