Peptide binding specificity of HLA-DR4 molecules: correlation with rheumatoid arthritis association.
Peptide binding specificity of HLA-DR4 molecules: correlation with rheumatoid arthritis association.
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DOI：
10.1084/jem.181.5.1847
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发表时间：
1995-05-01
期刊：
影响因子：
--
通讯作者：
Sinigaglia F
中科院分区：
文献类型：
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作者：
Hammer J;Gallazzi F;Bono E;Karr RW;Guenot J;Valsasnini P;Nagy ZA;Sinigaglia F
我们已经研究了类风湿性关节炎（RA）相关的HLA-DR分子的β链共享的序列67至74是否赋予肽结合的特定模式。因此，使用设计肽库确定RA相关分子DRB 1 *0401、DRB 1 *0404和密切相关的RA非相关DRB 1 *0402的肽结合特异性。用DRB 1 *0401的定点突变体测试单个关键残基的作用。结果表明，在选择与67-74区域相互作用的肽部分方面，RA连锁和非连锁DR同种异型之间存在显著差异。大多数差异与DR β链第71位的单个氨基酸交换相关，并影响可能接触第71位的残基的电荷。观察到的结合模式允许一个准确的预测天然蛋白质衍生的肽序列，选择性结合RA相关的DR分子。因此，67-74区域，特别是位置71，诱导与RA易感性的遗传连锁相关的结合特异性的变化。这些发现将有助于识别参与RA发病机制的自身抗原肽。
We have investigated whether sequence 67 to 74 shared by beta chains of rheumatoid arthritis (RA)-associated HLA-DR molecules imparts a specific pattern of peptide binding. The peptide binding specificity of the RA-associated molecules, DRB1*0401, DRB1*0404, and the closely related, RA nonassociated DRB1*0402 was, therefore, determined using designer peptide libraries. The effect of single key residues was tested with site-directed mutants of DRB1*0401. The results have demonstrated striking differences between RA-linked and unlinked DR allotypes in selecting the portion of peptides that interacts with the 67-74 area. Most differences were associated with a single amino acid exchange at position 71 of the DR beta chain, and affected the charge of residues potentially contacting position 71. The observed binding patterns permitted an accurate prediction of natural protein derived peptide sequences that bind selectively to RA-associated DR molecules. Thus, the 67-74 region, in particular position 71, induces changes of binding specificity that correlate with the genetic linkage of RA susceptibility. These findings should facilitate the identification of autoantigenic peptides involved in the pathogenesis of RA.