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Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells

Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells
Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells
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 Å 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.
0027-8424
E1266-E1275
Mansour, Salah
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Tocheva, Anna
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Cave-Ayland, Chris
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Machelett, Moritz M.
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Sander, Barbara
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Lissin, Nikolai M.
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Molloy, Peter E.
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Baird, Mark S.
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Stubs, Gunthard
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Schroder, Nicolas W.J.
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Schumann, Ralf R.
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Rademann, Jorg
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Postle, Anthony D.
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Jakobsen, Bent K.
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Marshall, Ben G.
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Gosain, Rajendra
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Elkington, Paul
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Elliott, Tim
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Skylaris, Chris-Kriton
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Essex, Jonathan W.
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Tews, Ivo
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Gadola, Stephan D.
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Mansour, Salah
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Tocheva, Anna
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Cave-Ayland, Chris
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Machelett, Moritz M.
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Sander, Barbara
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Lissin, Nikolai M.
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Molloy, Peter E.
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Baird, Mark S.
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Stubs, Gunthard
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Schroder, Nicolas W.J.
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Schumann, Ralf R.
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Rademann, Jorg
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Postle, Anthony D.
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Jakobsen, Bent K.
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Marshall, Ben G.
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Gosain, Rajendra
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Elkington, Paul
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Elliott, Tim
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Skylaris, Chris-Kriton
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Essex, Jonathan W.
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Tews, Ivo
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Gadola, Stephan D.
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Mansour, Salah, Tocheva, Anna, Cave-Ayland, Chris, Machelett, Moritz M., Sander, Barbara, Lissin, Nikolai M., Molloy, Peter E., Baird, Mark S., Stubs, Gunthard, Schroder, Nicolas W.J., Schumann, Ralf R., Rademann, Jorg, Postle, Anthony D., Jakobsen, Bent K., Marshall, Ben G., Gosain, Rajendra, Elkington, Paul, Elliott, Tim, Skylaris, Chris-Kriton, Essex, Jonathan W., Tews, Ivo and Gadola, Stephan D. (2016) Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells. Proceedings of the National Academy of Sciences, 113 (9), E1266-E1275. (doi:10.1073/pnas.1519246113). (PMID:26884207)

Record type: Article

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 Å 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.

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Accepted/In Press date: 21 January 2016
e-pub ahead of print date: 16 February 2016
Published date: 1 March 2016
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 386585
URI: http://eprints.soton.ac.uk/id/eprint/386585
ISSN: 0027-8424
PURE UUID: cbefe3cd-df68-4f9c-9fb6-314371276ba2
ORCID for Salah Mansour: ORCID iD orcid.org/0000-0002-5982-734X
ORCID for Anthony D. Postle: ORCID iD orcid.org/0000-0001-7361-0756
ORCID for Paul Elkington: ORCID iD orcid.org/0000-0003-0390-0613
ORCID for Tim Elliott: ORCID iD orcid.org/0000-0003-1097-0222
ORCID for Chris-Kriton Skylaris: ORCID iD orcid.org/0000-0003-0258-3433
ORCID for Jonathan W. Essex: ORCID iD orcid.org/0000-0003-2639-2746
ORCID for Ivo Tews: ORCID iD orcid.org/0000-0002-4704-1139

Catalogue record

Date deposited: 29 Jan 2016 12:39
Last modified: 07 Oct 2020 07:37

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Contributors

Author: Salah Mansour ORCID iD
Author: Anna Tocheva
Author: Chris Cave-Ayland
Author: Moritz M. Machelett
Author: Barbara Sander
Author: Nikolai M. Lissin
Author: Peter E. Molloy
Author: Mark S. Baird
Author: Gunthard Stubs
Author: Nicolas W.J. Schroder
Author: Ralf R. Schumann
Author: Jorg Rademann
Author: Bent K. Jakobsen
Author: Ben G. Marshall
Author: Rajendra Gosain
Author: Paul Elkington ORCID iD
Author: Tim Elliott ORCID iD
Author: Ivo Tews ORCID iD
Author: Stephan D. Gadola

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