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Peptide-independent stabilization of MHC class I molecules breaches cellular quality control

Peptide-independent stabilization of MHC class I molecules breaches cellular quality control
Peptide-independent stabilization of MHC class I molecules breaches cellular quality control
The intracellular trafficking of major histocompatibility complex class I (MHC-I) proteins is directed by three quality control mechanisms that test for their structural integrity, which is correlated to the binding of high-affinity antigenic peptide ligands. To investigate which molecular features of MHC-I these quality control mechanisms detect, we have followed the hypothesis that suboptimally loaded MHC-I molecules are characterized by their conformational mobility in the F-pocket region of the peptide-binding site. We have created a novel variant of an MHC-I protein, Kb-Y84C, in which two ?-helices in this region are linked by a disulfide bond that mimics the conformational and dynamic effects of bound high-affinity peptide. Kb-Y84C shows a remarkable increase in the binding affinity to its light chain, beta-2 microglobulin (?2m), and bypasses all three cellular quality control steps. Our data demonstrate (1) that coupling between peptide and ?2m binding to the MHC-I heavy chain is mediated by conformational dynamics; (2) that the folded conformation of MHC-I, supported by ?2m, plays a decisive role in passing the ER-to-cell-surface transport quality controls; and (3) that ?2m association is also tested by the cell surface quality control that leads to MHC-I endocytosis.
antigen presentation, endocytosis, major histocompatibility complex, ER quality control
0021-9533
2885-2897
Hein, Z.
27acaed8-6e64-4c73-9774-f158c7cd083a
Uchtenhagen, H.
3b001146-d2e3-4b45-96cd-8f79bf13ae4e
Abualrous, E.T.
29b5a816-d73a-44d6-8acb-e4791ca54b7a
Saini, S.K.
4112486d-f0b6-40db-bc85-41e8bfcb6010
Janssen, L.
f38338d7-d87e-4f45-9b21-8188ccbb5d2a
Van Hateren, A.
e345fa3c-d89c-4b91-947e-c1d818cc7f71
Wiek, C.
1318047a-3f46-4686-8932-48d51334ceb1
Hanenberg, H.
9be0e756-94fe-40f7-aca3-8e3b817a0cac
Momburg, F.
46055778-2e8f-4e73-bb6d-08fc9aa1b81c
Achour, A.
00e6b2dd-05b0-4410-ae0e-e8b02c07a49e
Elliott, T.
16670fa8-c2f9-477a-91df-7c9e5b453e0e
Springer, S.
9ca11f1a-56b1-48d3-895b-b5609e7fab8c
Boulanger, D.
c226ad99-9c9a-485a-b480-42fb8799120f
Hein, Z.
27acaed8-6e64-4c73-9774-f158c7cd083a
Uchtenhagen, H.
3b001146-d2e3-4b45-96cd-8f79bf13ae4e
Abualrous, E.T.
29b5a816-d73a-44d6-8acb-e4791ca54b7a
Saini, S.K.
4112486d-f0b6-40db-bc85-41e8bfcb6010
Janssen, L.
f38338d7-d87e-4f45-9b21-8188ccbb5d2a
Van Hateren, A.
e345fa3c-d89c-4b91-947e-c1d818cc7f71
Wiek, C.
1318047a-3f46-4686-8932-48d51334ceb1
Hanenberg, H.
9be0e756-94fe-40f7-aca3-8e3b817a0cac
Momburg, F.
46055778-2e8f-4e73-bb6d-08fc9aa1b81c
Achour, A.
00e6b2dd-05b0-4410-ae0e-e8b02c07a49e
Elliott, T.
16670fa8-c2f9-477a-91df-7c9e5b453e0e
Springer, S.
9ca11f1a-56b1-48d3-895b-b5609e7fab8c
Boulanger, D.
c226ad99-9c9a-485a-b480-42fb8799120f

Hein, Z., Uchtenhagen, H., Abualrous, E.T., Saini, S.K., Janssen, L., Van Hateren, A., Wiek, C., Hanenberg, H., Momburg, F., Achour, A., Elliott, T., Springer, S. and Boulanger, D. (2014) Peptide-independent stabilization of MHC class I molecules breaches cellular quality control Journal of Cell Science, 127, (13), pp. 2885-2897. (doi:10.1242/jcs.145334). (PMID:24806963).

Record type: Article

Abstract

The intracellular trafficking of major histocompatibility complex class I (MHC-I) proteins is directed by three quality control mechanisms that test for their structural integrity, which is correlated to the binding of high-affinity antigenic peptide ligands. To investigate which molecular features of MHC-I these quality control mechanisms detect, we have followed the hypothesis that suboptimally loaded MHC-I molecules are characterized by their conformational mobility in the F-pocket region of the peptide-binding site. We have created a novel variant of an MHC-I protein, Kb-Y84C, in which two ?-helices in this region are linked by a disulfide bond that mimics the conformational and dynamic effects of bound high-affinity peptide. Kb-Y84C shows a remarkable increase in the binding affinity to its light chain, beta-2 microglobulin (?2m), and bypasses all three cellular quality control steps. Our data demonstrate (1) that coupling between peptide and ?2m binding to the MHC-I heavy chain is mediated by conformational dynamics; (2) that the folded conformation of MHC-I, supported by ?2m, plays a decisive role in passing the ER-to-cell-surface transport quality controls; and (3) that ?2m association is also tested by the cell surface quality control that leads to MHC-I endocytosis.

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More information

e-pub ahead of print date: 7 May 2014
Published date: 1 July 2014
Keywords: antigen presentation, endocytosis, major histocompatibility complex, ER quality control
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 368149
URI: http://eprints.soton.ac.uk/id/eprint/368149
ISSN: 0021-9533
PURE UUID: dedcc22a-ea4f-4389-8a2e-b7fa8d4e722c
ORCID for T. Elliott: ORCID iD orcid.org/0000-0003-1097-0222

Catalogue record

Date deposited: 19 Aug 2014 10:06
Last modified: 18 Jul 2017 01:51

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Contributors

Author: Z. Hein
Author: H. Uchtenhagen
Author: E.T. Abualrous
Author: S.K. Saini
Author: L. Janssen
Author: A. Van Hateren
Author: C. Wiek
Author: H. Hanenberg
Author: F. Momburg
Author: A. Achour
Author: T. Elliott ORCID iD
Author: S. Springer
Author: D. Boulanger

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