Crystal structure of a polypeptide's C-terminus in complex with the regulatory domain of ER aminopeptidase
Crystal structure of a polypeptide's C-terminus in complex with the regulatory domain of ER aminopeptidase
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DOI：
10.1016/j.molimm.2016.10.012
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发表时间：
2016-12-01
影响因子：
3.6
通讯作者：
Guo, Hwai-Chen
中科院分区：
文献类型：
--
作者：
Sui, Lufei;Gandhi, Amit;Guo, Hwai-Chen
内质网氨肽酶 I (ERAP1) 参与肽前体的最终加工，以生成 MHC I 类限制性表位的 N 末端。因此，ERAP1 通过控制 MHC 分子可用于细胞表面呈递的肽库来影响免疫优势和细胞毒性免疫反应。为了在抗原加工中发挥这一关键作用，ERAP1 通过独特的分子标尺机制修剪肽，该机制以肽长度和序列依赖的方式打开/关闭水解活性。因此，与其他氨肽酶不同，ERAP1 可以识别肽的 N 端和 C 端，以便读取底物的长度。为了例证和验证这种分子标尺机制，我们对ERAP1对抗原肽C末端的分子识别进行了晶体学研究。在本报告中，我们确定了 ERAPI 调节域和融合蛋白中显示的天然表位 C 末端之间的分子间复合物的 2.8 埃分辨率晶体结构。它揭示了 ERAP1 识别肽 C 末端的结构细节。 ERAP1 使用调节域上的特异性口袋来结合肽的羧基端和 C 端锚定残基的侧链。同时，肽中间的长度和序列的灵活性通过与 ERAP1 相互作用最小化的扭结来调节。 (C) 2016 Elsevier Ltd. 保留所有权利。
Endoplasmic reticulum aminopeptidase I (ERAP1) is involved in the final processing of peptide precursors to generate the N-termini of MHC class I-restricted epitopes. ERAP1 thus influences immunodominance and cytotoxic immune responses by controlling the peptide repertoire available for cell surface presentation by MHC molecules. To enable this critical role in antigen processing, ERAP1 trims peptides by a unique molecular ruler mechanism that turns on/off hydrolysis activity in a peptide-length and sequence dependent manner. Thus unlike other aminopeptidases, ERAP1 could recognize both the Nand C-termini of peptides in order to read the substrate's length. To exemplify and validate this molecular ruler mechanism, we have carried out crystallographic studies on molecular recognition of antigenic peptide's C-terminus by ERAP1. In this report, we have determined a 2.8 angstrom-resolution crystal structure of an intermolecular complex between the ERAPI regulatory domain and a natural epitope's C-terminus displayed in a fusion protein. It reveals the structural details of peptide's C-termini recognition by ERAP1. ERAP1 uses specificity pockets on the regulatory domain to bind the peptide's carboxyl end and side chain of the C-terminal anchoring residue. At the same time, flexibility in length and sequence at the middle of peptides is accommodated by a kink with minimal interactions with ERAP1. (C) 2016 Elsevier Ltd. All rights reserved.