7MWC

ERAP1 binds peptide C-terminus of a LPF sequence (AAAAFKARKF)

7MWC の概要

• エントリーDOI: 10.2210/pdb7mwc/pdb
• 関連するPDBエントリー: 7MWB
• 分子名称: Endoplasmic reticulum aminopeptidase 1,LPF sequence (2 entities in total)
• 機能のキーワード: antigen presentation, erap1 molecular ruler mechanism, hydrolase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 195808.67

構造登録者

Guo, H.C.,Sui, L. (登録日: 2021-05-16, 公開日: 2021-07-28, 最終更新日: 2023-10-18)

主引用文献

Sui, L.,Guo, H.C.
ERAP1 binds peptide C-termini of different sequences and/or lengths by a common recognition mechanism.
Immunobiology, 226:152112-152112, 2021

PubMed Abstract: 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.

PubMed: 34247019
DOI: 10.1016/j.imbio.2021.152112

実験手法

X-RAY DIFFRACTION (3 Å)