Citrullination-dependent differential presentation of a self-peptide by HLA-B27 subtypes
Citrullination-dependent differential presentation of a self-peptide by HLA-B27 subtypes
复制标题
DOI：
10.1074/jbc.m802818200
复制
发表时间：
2008-10-03
影响因子：
4.8
通讯作者：
Uchanska-Ziegler, Barbara
中科院分区：
文献类型：
--
作者：
Beltrami, Alessandra;Rossmann, Maxim;Uchanska-Ziegler, Barbara
炎症过程伴随着蛋白质内某些精氨酸残基的翻译后修饰以产生瓜氨酸，尽管这种修饰如何影响抗原呈递在很大程度上是未知的。我们采用晶体学和功能研究来研究精氨酸与瓜氨酸的交换是否影响两种人类主要组织相容性抗原I类亚型HLA-B* 2705和HLA-B* 2709对肽的展示。两者仅在肽结合沟内的残基116上不同，尽管它们与强直性脊柱炎（一种炎性风湿性疾病）有不同的关联。此处描述的晶体结构表明，修饰的自身肽pVIPR-U 5（RRKWURWHL; U =瓜氨酸）由两种HLA-B27分子以不同的构象呈递。这些结合模式不仅彼此显著不同，而且与给定亚型中非瓜氨酸化肽所表现出的构象也不同。HLA-B27限制性细胞毒性T细胞与修饰或未修饰的pVIPR的不同反应性支持了结构发现，并表明瓜氨酸化肽的呈递具有影响免疫应答的潜力。
Inflammatory processes are accompanied by the posttranslational modification of certain arginine residues within proteins to yield citrulline, although it is largely unknown how this modification influences antigen presentation. We employed crystallographic and functional studies to investigate whether the exchange of arginine to citrulline affects the display of a peptide by two human major histocompatibility antigen class I subtypes, HLA-B* 2705 and HLA-B* 2709. Both differ only in residue 116 within the peptide binding groove despite their differential association with ankylosing spondylitis, an inflammatory rheumatic disorder. The crystal structures described here show that a modified self-peptide, pVIPR-U5(RRKWURWHL; U = citrulline), is presented by the two HLA-B27 molecules in distinct conformations. These binding modes differ not only drastically from each other but also from the conformations exhibited by the non-citrullinated peptide in a given subtype. The differential reactivity of HLA-B27-restricted cytotoxic T cells with modified or unmodified pVIPR supports the structural findings and shows that the presentation of citrullinated peptides has the potential to influence immune responses.