C-terminal modification of the insulin B: 11-23 peptide creates superagonists in mouse and human type 1 diabetes

Wang Yang; Sosinowski Tomasz; Novikov AndreyCrawford FrancesNeau David B.Yang JunbaoKwok William W.Marrack PhilippaKappler John W.Dai Shaodong

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C-terminal modification of the insulin B: 11-23 peptide creates superagonists in mouse and human type 1 diabetes

机译：C-terminal modification of the insulin B: 11-23 peptide creates superagonists in mouse and human type 1 diabetes

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Apolymorphismat beta 57 in some major histocompatibility complex class II (MHCII) alleles of rodents and humans is associated with a high risk for developing type 1 diabetes (T1D). However, a highly diabetogenic insulin B chain epitope within the B: 9-23 peptide is presented poorly by these alleles to a variety of mouse and human CD4 T cells isolated from either nonobese diabetic (NOD) mice or humans with T1D. We have shown for both species that mutations at the C-terminal end of this epitope dramatically improve presentation to these T cells. Here we present the crystal structures of these mutated peptides bound to mouse IAg97 and human HLA-DQ8 that show how the mutations function to improve T-cell activation. In both peptide binding grooves, the mutation of B:22R to E in the peptide changes a highly unfavorable side chain for the p9 pocket to an optimal one that is dependent on the beta 57 polymorphism, accounting for why these peptides bind much better to these MHCIIs. Furthermore, a second mutation of the adjacent B: 21 (E to G) removes a side chain from the surface of the complex that is highly unfavorable for a subset of NOD mouse CD4 cells, thereby greatly enhancing their response to the complex. These results point out the similarities between the mouse and human responses to this B chain epitope in T1D and suggest there may be common posttranslational modifications at the C terminus of the peptide in vivo to create the pathogenic epitopes in both species.

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《Proceedings of the National Academy of Sciences of the United States of America.》 |2018年第1期|162-167|共6页
作者
Wang Yang; Sosinowski Tomasz; Novikov AndreyCrawford FrancesNeau David B.Yang JunbaoKwok William W.Marrack PhilippaKappler John W.Dai Shaodong;
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作者单位

Natl Jewish Hlth, Dept Biomed Res, Denver, CO 80206 USA;

Univ Colorado, Barbara Davis Ctr Childhood Diabet, Aurora, CO 80045 USA;

Cornell Univ, Northeastern Collaborat Access Team, Lemont, IL 60349 USABenaroya Res Inst, Diabet Res Program, Seattle, WA 98101 USA;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
autoimmunity; peptide presentation; self-tolerance; posttranslational modification;

C-terminal modification of the insulin B: 11-23 peptide creates superagonists in mouse and human type 1 diabetes

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