The internal sequence of the peptide-substrate determines its N-terminus trimming by ERAP1.
The internal sequence of the peptide-substrate determines its N-terminus trimming by ERAP1.
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DOI：
10.1371/journal.pone.0003658
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发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Stratikos E
中科院分区：
文献类型：
--
作者：
Evnouchidou I;Momburg F;Papakyriakou A;Chroni A;Leondiadis L;Chang SC;Goldberg AL;Stratikos E
内质网氨肽酶1（ERAP 1）将N-末端延伸的抗原肽前体修剪成成熟的抗原肽，以供主要组织相容性复合体（MHC）I类分子呈递。ERAP 1具有独特的氨肽酶特性，能够根据肽的长度和C-末端的性质在体外修剪肽。为了更好地理解ERAP 1用于修饰肽的分子机制，我们使用肽底物的集合系统地分析了酶的底物偏好。我们发现了ERAP 1对肽N-末端修剪的强烈的内部序列偏好。仅发现对带正电荷或疏水残基的偏好，导致对于具有相同N-末端的肽，单个残基取代的修整速率变化高达100倍，并且多个残基取代的修整速率变化超过40，000倍。ERAP 1的分子模型揭示了一个大的内部空腔，该空腔携带强大的负静电势，并且足够大以容纳邻近酶活性位点的肽。该模型可以很容易地解释对带正电荷的侧链的强烈偏好。据我们所知，没有其他氨肽酶被描述为具有如此强烈的偏好的内部残基，所以远端的N-末端。总的来说，我们的研究结果表明，肽的内部序列可以影响其修剪ERAP 1一样多的肽的长度和C-末端。因此，我们提出ERAP 1识别其肽底物的全长，而不仅仅是N-和C-末端。ERAP 1修剪偏好可能影响体内抗原肽的生成速率和组成。
Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims N-terminally extended antigenic peptide precursors down to mature antigenic peptides for presentation by major histocompatibility complex (MHC) class I molecules. ERAP1 has unique properties for an aminopeptidase being able to trim peptides in vitro based on their length and the nature of their C-termini. In an effort to better understand the molecular mechanism that ERAP1 uses to trim peptides, we systematically analyzed the enzyme's substrate preferences using collections of peptide substrates. We discovered strong internal sequence preferences of peptide N-terminus trimming by ERAP1. Preferences were only found for positively charged or hydrophobic residues resulting to trimming rate changes by up to 100 fold for single residue substitutions and more than 40,000 fold for multiple residue substitutions for peptides with identical N-termini. Molecular modelling of ERAP1 revealed a large internal cavity that carries a strong negative electrostatic potential and is large enough to accommodate peptides adjacent to the enzyme's active site. This model can readily account for the strong preference for positively charged side chains. To our knowledge no other aminopeptidase has been described to have such strong preferences for internal residues so distal to the N-terminus. Overall, our findings indicate that the internal sequence of the peptide can affect its trimming by ERAP1 as much as the peptide's length and C-terminus. We therefore propose that ERAP1 recognizes the full length of its peptide-substrate and not just the N- and C- termini. It is possible that ERAP1 trimming preferences influence the rate of generation and the composition of antigenic peptides in vivo.
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DOI：
10.1084/jem.190.9.1227
发表时间：
1999-11-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lauvau G;Kakimi K;Niedermann G;Ostankovitch M;Yotnda P;Firat H;Chisari FV;van Endert PM
通讯作者：
van Endert PM
DOI：
10.1084/jem.180.5.1591
发表时间：
1994-11-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Roelse J;Grommé M;Momburg F;Hämmerling G;Neefjes J
通讯作者：
Neefjes J
影响因子：
4.8
作者：
Saric, T;Beninga, J;Goldberg, AL
通讯作者：
Goldberg, AL
影响因子：
64.8
作者：
MOMBURG, F;ROELSE, J;NEEFJES, JJ
通讯作者：
NEEFJES, JJ
影响因子：
2.7
作者：
Hattori, A;Matsumoto, H;Tsujimoto, M
通讯作者：
Tsujimoto, M