The ER aminopeptidase, ERAN1, trims precursors to lengths of MHC class I peptides by a "molecular ruler" mechanism
The ER aminopeptidase, ERAN1, trims precursors to lengths of MHC class I peptides by a "molecular ruler" mechanism
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DOI：
10.1073/pnas.0500721102
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发表时间：
2005-11-22
影响因子：
11.1
通讯作者：
Goldberg, AL
中科院分区：
文献类型：
--
作者：
Chang, SC;Momburg, F;Goldberg, AL
内质网氨肽酶 1 (ERAP1) 是内质网中 IFN-γ 诱导的氨肽酶，可修剪 MHC I 类分子上呈递的抗原肽的较长前体。我们最近报道，纯化的 ERAP1 修剪了 N 延伸前体，但保留了 8 - 9 个残基的肽，这是与 MHC I 类分子结合所需的长度。在这里，我们展示了 ERAP1 的另一个显着特性：它强烈偏爱 9-16 个残基长的底物，该长度的肽通过与抗原加工 (TAP) 转运蛋白相关的转运蛋白有效转运到 ER 中。即使底物和产物具有相同的 N 端和 C 端序列，该氨肽酶仍能快速将模型 13 聚体降解为 9 聚体，然后停止。没有其他氨肽酶，包括密切相关的 EIR-氨肽酶 ERAP2，表现出类似的长度偏好。与其他氨肽酶不同，ERAP1 的活性取决于底物的 C 端残基。与大多数 MHC I 类分子一样，ERAP1 更喜欢具有疏水性 C 末端的肽，并且对带电荷 C 末端的肽表现出低亲和力。因此，ERAP1 专门处理由 TAP 转运至可充当 MHC I 类表位的 peptices 的前体。其“分子标尺”机制涉及结合距活性位点9 -16 个残基的底物疏水C 末端。
Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an IFN-gamma-induced aminopeptidase in the endoplasmic reticulum that trims longer precursors to the antigenic peptides presented on MHC class I molecules. We recently reported that purified ERAP1 trimmed N-extended precursors but spared peptides of 8 - 9 residues, the length required for binding to MHC class I molecules. Here, we show another remarkable property of ERAP1: that it strongly prefers substrates 9 - 16 residues long, the lengths of pepticles transported efficiently into the ER by the transporter associated with antigen processing (TAP) transporter. This aminopeptidase rapidly degraded a model 13-mer to a 9-mer and then stopped, even though the substrate and the product had identical N- and C-terminal sequences. No other aminopeptidase, including the closely related EIR-aminopeptidase ERAP2, showed a similar length preference. Unlike other aminopeptidases, the activity of ERAP1 depended on the C-terminal residue of the substrate. ERAP1, like most MHC class I molecules, prefers pepticles with hydrophobic C termini and shows low affinity for peptides with charged C termini. Thus, ERAP1 is specialized to process precursors transported by TAP to pepticles that can serve as MHC class I epitopes. Its "molecular ruler" mechanism involves binding the hydrophobic C terminus of the substrate 9 -16 residues away from the active site.