title: HLA-B27 misfolding is associated with aberrant intermolecular disulfide bond formation (dimerization) in the endoplasmic reticulum.
abstract: The class I protein HLA-B27 confers susceptibility to inflammatory arthritis in humans and when overexpressed in rodents for reasons that remain unclear. We demonstrated previously that HLA-B27 heavy chains (HC) undergo endoplasmic reticulum (ER)-associated degradation. We report here that HLA-B27 HC also forms two types of aberrant disulfide-linked complexes (dimers) during the folding and assembly process that can be distinguished by conformation-sensitive antibodies W6/32 and HC10. HC10-reactive dimers form immediately after HC synthesis in the ER and constitute at least 25% of the HC pool, whereas W6/32-reactive dimers appear several hours later and represent less than 10% of the folded HC. HC10-reactive dimers accumulate in the absence of tapasin or beta(2)-microglobulin, whereas W6/32-reactive dimers are not detected. Efficient formation of W6/32-reactive dimers appears to depend on the transporter associated with antigen processing, tapasin, and beta(2)-microglobulin. The unpaired Cys(67) and residues at the base of the B pocket that dramatically impair HLA-B27 HC folding are critical for the formation of HC10-reactive ER dimers. Although certain other alleles also form dimers late in the assembly pathway, ER dimerization of HLA-B27 may be unique. These results demonstrate that residues comprising the HLA-B27 B pocket result in aberrant HC folding and disulfide bond formation, and thus confer unusual properties on this molecule that are unrelated to peptide selection per se, yet may be important in disease pathogenesis.
authors.affiliation: William S. Rowe Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA.
authors.forename: Nandita S
authors.initials: NS
authors.lastname: Dangoria
authors.forename: Monica L
authors.initials: ML
authors.lastname: DeLay
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Kingsbury
authors.forename: John P
authors.initials: JP
authors.lastname: Mear
authors.forename: Barbara
authors.initials: B
authors.lastname: Uchanska-Ziegler
authors.forename: Andreas
authors.initials: A
authors.lastname: Ziegler
authors.forename: Robert A
authors.initials: RA
authors.lastname: Colbert
mesh_terms: D017920:Antiporters / Q000502:physiology; D002460:Cell Line; D003545:Cysteine / Q000737:chemistry; D019281:Dimerization; D004220:Disulfides / Q000737:chemistry*; D004721:Endoplasmic Reticulum / Q000737:chemistry*; D015796:HLA-B27 Antigen / Q000737:chemistry*; D006801:Humans; D007136:Immunoglobulins / Q000502:physiology; D026901:Membrane Transport Proteins; D029543:Nucleocytoplasmic Transport Proteins; D017510:Protein Folding; D011506:Proteins / Q000502:physiology; D016601:RNA-Binding Proteins; D001613:beta 2-Microglobulin / Q000502:physiology
chemical_list: D017920:Antiporters; D004220:Disulfides; D015796:HLA-B27 Antigen; D007136:Immunoglobulins; D026901:Membrane Transport Proteins; C122111:NXF1 protein, human; D029543:Nucleocytoplasmic Transport Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; D001613:beta 2-Microglobulin; C107762:tapasin; D003545:Cysteine