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Formation of HLA-B27 homodimers and their relationship to assembly kinetics

Formation of HLA-B27 homodimers and their relationship to assembly kinetics
Formation of HLA-B27 homodimers and their relationship to assembly kinetics
The human HLA-B27 class I molecule exhibits a strong association with the inflammatory arthritic disorder ankylosing spondylitis and other related arthropathies. Major histocompatibility complex class I heavy chains normally associate with 2-microglobulin and peptide in the endoplasmic reticulum before transit to the cell surface. However, an unusual characteristic of HLA-B27 is its ability to form heavy chain homodimers through an unpaired cysteine at position 67 in the peptide groove. Homodimers have previously been detected within the ER and at the cell surface, but their mechanism of formation and role in disease remain undefined. Here we demonstrate, in the rat C58 thymoma cell line and in human HeLa cells transfected with HLA-B27, that homodimer formation involves not only cysteine at position 67 but also the conserved structural cysteine at position 164. We also show that homodimer formation can be induced in the non-disease-associated HLA class I allele HLA-A2 by slowing its assembly rate by incubation of cells at 26 °C, suggesting that homodimer formation in the endoplasmic reticulum may occur as a result of the slower folding kinetics of HLA-B27. Finally, we report an association between unfolded HLA-B27 molecules and immunoglobulin-binding protein at the cell surface.
0021-9258
8895-8902
Antoniou, Antony N.
3d711a3b-f688-46f9-823e-5bb925d10ea8
Ford, Stuart
911cc21c-13b6-42ff-bb0b-ba0d01ba1a42
Taurog, Joel D.
e49797f4-d7db-4dbc-881a-1d838380017b
Butcher, Geoffrey W.
a5c49811-cab8-46b3-80d6-e16aaa244c07
Powis, Simon J.
1bdcdc68-9097-459d-9675-7bb408316bf9
Antoniou, Antony N.
3d711a3b-f688-46f9-823e-5bb925d10ea8
Ford, Stuart
911cc21c-13b6-42ff-bb0b-ba0d01ba1a42
Taurog, Joel D.
e49797f4-d7db-4dbc-881a-1d838380017b
Butcher, Geoffrey W.
a5c49811-cab8-46b3-80d6-e16aaa244c07
Powis, Simon J.
1bdcdc68-9097-459d-9675-7bb408316bf9

Antoniou, Antony N., Ford, Stuart, Taurog, Joel D., Butcher, Geoffrey W. and Powis, Simon J. (2004) Formation of HLA-B27 homodimers and their relationship to assembly kinetics. The Journal of Biological Chemistry, 279 (10), 8895-8902. (doi:10.1074/jbc.M311757200).

Record type: Article

Abstract

The human HLA-B27 class I molecule exhibits a strong association with the inflammatory arthritic disorder ankylosing spondylitis and other related arthropathies. Major histocompatibility complex class I heavy chains normally associate with 2-microglobulin and peptide in the endoplasmic reticulum before transit to the cell surface. However, an unusual characteristic of HLA-B27 is its ability to form heavy chain homodimers through an unpaired cysteine at position 67 in the peptide groove. Homodimers have previously been detected within the ER and at the cell surface, but their mechanism of formation and role in disease remain undefined. Here we demonstrate, in the rat C58 thymoma cell line and in human HeLa cells transfected with HLA-B27, that homodimer formation involves not only cysteine at position 67 but also the conserved structural cysteine at position 164. We also show that homodimer formation can be induced in the non-disease-associated HLA class I allele HLA-A2 by slowing its assembly rate by incubation of cells at 26 °C, suggesting that homodimer formation in the endoplasmic reticulum may occur as a result of the slower folding kinetics of HLA-B27. Finally, we report an association between unfolded HLA-B27 molecules and immunoglobulin-binding protein at the cell surface.

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More information

Published date: 5 March 2004

Identifiers

Local EPrints ID: 26201
URI: http://eprints.soton.ac.uk/id/eprint/26201
ISSN: 0021-9258
PURE UUID: fc1ddf5b-45ee-41c0-9eaa-933e7e860271

Catalogue record

Date deposited: 20 Apr 2006
Last modified: 15 Jul 2019 19:14

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