title: Formation of HLA-B27 homodimers and their relationship to assembly kinetics.
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 beta(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 degrees 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.
authors.affiliation: Division of Cell Biology and Immunology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom.
authors.forename: Antony N
authors.initials: AN
authors.lastname: Antoniou
authors.forename: Stuart
authors.initials: S
authors.lastname: Ford
authors.forename: Joel D
authors.initials: JD
authors.lastname: Taurog
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Butcher
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Powis
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003545:Cysteine; D019281:Dimerization; D015796:HLA-B27 Antigen / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D017510:Protein Folding; D051381:Rats; D013696:Temperature
chemical_list: D015796:HLA-B27 Antigen; D003545:Cysteine