Formation of HLA-B27 homodimers and their relationship to assembly kinetics
Formation of HLA-B27 homodimers and their relationship to assembly kinetics
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DOI：
10.1074/jbc.m311757200
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发表时间：
2004-03-05
影响因子：
4.8
通讯作者：
Powis, SJ
中科院分区：
文献类型：
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作者：
Antoniou, AN;Ford, S;Powis, SJ
人类人类白细胞抗原-B27-I类分子与炎症性关节炎、强直性脊柱炎和其他相关关节疾病有很强的相关性。主要组织相容性复合体I类重链通常在转运到细胞表面之前与内质网中的β(2)-微球蛋白和多肽结合。然而，人类白细胞抗原-B27的一个不同寻常的特征是它能够通过位于肽槽67位的未配对的半胱氨酸形成重链同源二聚体。以前已经在内质网和细胞表面检测到同源二聚体，但它们的形成机制和在疾病中的作用仍不清楚。在此，我们证明，在大鼠C58胸腺瘤细胞系和转导了人类白细胞抗原-B27的人HeLa细胞中，同源二聚体的形成不仅包括67位半胱氨酸，还包括164位保守结构半胱氨酸。我们还发现，在26℃的细胞孵育中，通过减缓非疾病相关的HLA-I类等位基因的组装速度，可以在非疾病相关的HLA-I类等位基因HLA-A2中诱导同源二聚体的形成，这表明内质网中的同源二聚体的形成可能是由于HLA-B27折叠动力学较慢的结果。最后，我们报道了未折叠的人类白细胞抗原-B27分子与细胞表面的免疫球蛋白结合蛋白之间的关系。
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 26degreesC, 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.