ERAP1 binds peptide C-termini of different sequences and/or lengths by a common recognition mechanism.
ERAP1 binds peptide C-termini of different sequences and/or lengths by a common recognition mechanism.
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DOI：
10.1016/j.imbio.2021.152112
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发表时间：
2021-07
期刊：
影响因子：
2.8
通讯作者：
Guo HC
中科院分区：
文献类型：
--
作者：
Sui L;Guo HC
内质网氨肽酶1（ERAP 1）在控制免疫肽段被主要组织相容性复合物（MHC）分子提呈中起关键作用，从而影响免疫优势和细胞免疫。它通过以肽长度和序列依赖性方式修剪抗原前体的独特分子统治者机制来执行这一关键功能。ERAP 1作为分子标尺，能够分别通过其N端催化结构域和C端调节结构域同时结合抗原肽的N端和C端。因此，ERAP 1不仅可以监测底物的长度，而且还在底物的N-和C-末端表现出一定程度的序列特异性。另一方面，它还允许肽底物的中间部分具有一定的序列和长度灵活性，这对于形成MHC限制性免疫肽段至关重要。在这里，我们报告了结构和生化研究，以了解ERAP 1如何容纳底物C末端不同锚定残基的侧链的分子细节。我们还研究了ERAP 1如何能够容纳具有长度灵活性的抗原肽前体。基于两个新确定的复合物结构，我们发现ERAP 1通过利用相同的疏水特异性口袋来容纳具有Phe或Leu作为C-末端锚残基的肽，即使具有不同的底物序列和/或长度，也类似地结合肽的C-末端。此外，溶液中的SPR（表面等离子体共振）结合分析进一步证实了这些肽-ERAP 1相互作用的生物学意义。与MHC-I分子的结合模式相似，ERAP 1通过允许肽中间部分在其底物结合裂缝的中间扭结或凸起来适应抗原肽长度差异。这解释了位于ERAP 1底物结合裂缝中间的SNP编码变体如何影响抗原库和个体对疾病的易感性。
Endoplasmic reticulum aminopeptidase 1 (ERAP1) plays a key role in controlling the immunopeptidomes available for presentation by MHC (major histocompatibility complex) molecules, thus influences immunodominance and cell-mediated immunity. It carries out this critical function by a unique molecular ruler mechanism that trims antigenic precursors in a peptide-length and sequence dependent manner. Acting as a molecular ruler, ERAP1 is capable of concurrently binding antigen peptide N- and C-termini by its N-terminal catalytic and C-terminal regulatory domains, respectively. As such ERAP1 can not only monitor substrate’s lengths, but also exhibit a degree of sequence specificity at substrates’ N- and C-termini. On the other hand, it also allows certain sequence and length flexibility in the middle part of peptide substrates that is critical for shaping MHC restricted immunopeptidomes. Here we report structural and biochemical studies to understand the molecular details on how ERAP1 can accommodate side chains of different anchoring residues at the substrate’s C-terminus. We also examine how ERAP1 can accommodate antigen peptide precursors with length flexibility. Based on two newly determined complex structures, we find that ERAP1 binds the C-termini of peptides similarly even with different substrate sequences and/or lengths, by utilizing the same hydrophobic specificity pocket to accommodate peptides with either a Phe or Leu as the C-terminal anchor residue. In addition, SPR (surface plasmon resonance) binding analyses in solution further confirm the biological significance of these peptide-ERAP1 interactions. Similar to the binding mode of MHC-I molecules, ERAP1 accommodates for antigenic peptide length difference by allowing the peptide middle part to kink or bulge at the middle of its substrate binding cleft. This explains how SNP coded variants located at the middle of ERAP1 substrate binding cleft would influence the antigen pool and an individual’s susceptibility to diseases.
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DOI：
10.1107/s0907444911007232
发表时间：
2011-04
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Krissinel E
通讯作者：
Krissinel E
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
7
作者：
Guasp, Pablo;Lorente, Elena;Lopez de Castro, Jose A.
通讯作者：
Lopez de Castro, Jose A.
DOI：
10.1073/pnas.90.17.8053
发表时间：
1993-09-01
影响因子：
11.1
作者：
GUO, HC;MADDEN, DR;WILEY, DC
通讯作者：
WILEY, DC
影响因子：
2.7
作者：
Hanson, Aimee L.;Morton, Craig J.;Kenna, Tony J.
通讯作者：
Kenna, Tony J.