4E36

Crystal structure of the human Endoplasmic Reticulum Aminopeptidase 2 variant N392K

4E36 の概要

• エントリーDOI: 10.2210/pdb4e36/pdb
• 関連するPDBエントリー: 3SE6
• 分子名称: Endoplasmic reticulum aminopeptidase 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-4)-alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• 機能のキーワード: thermolysin-like catalytic domain, hydrolase, aminopeptidase, zinc binding, glycosylation, endoplasmic reticulum
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 226783.30

構造登録者

Birtley, J.R.,Saridakis, E.,Pegias, P.,Stratikos, E.,Mavridis, I.M. (登録日: 2012-03-09, 公開日: 2012-08-29, 最終更新日: 2024-10-09)

主引用文献

Evnouchidou, I.,Birtley, J.,Seregin, S.,Papakyriakou, A.,Zervoudi, E.,Samiotaki, M.,Panayotou, G.,Giastas, P.,Petrakis, O.,Georgiadis, D.,Amalfitano, A.,Saridakis, E.,Mavridis, I.M.,Stratikos, E.
A common single nucleotide polymorphism in endoplasmic reticulum aminopeptidase 2 induces a specificity switch that leads to altered antigen processing.
J.Immunol., 189:2383-2392, 2012

PubMed Abstract: Endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2) cooperate to trim antigenic peptide precursors for loading onto MHC class I molecules and help regulate the adaptive immune response. Common coding single nucleotide polymorphisms in ERAP1 and ERAP2 have been linked with predisposition to human diseases ranging from viral and bacterial infections to autoimmunity and cancer. It has been hypothesized that altered Ag processing by these enzymes is a causal link to disease etiology, but the molecular mechanisms are obscure. We report in this article that the common ERAP2 single nucleotide polymorphism rs2549782 that codes for amino acid variation N392K leads to alterations in both the activity and the specificity of the enzyme. Specifically, the 392N allele excises hydrophobic N-terminal residues from epitope precursors up to 165-fold faster compared with the 392K allele, although both alleles are very similar in excising positively charged N-terminal amino acids. These effects are primarily due to changes in the catalytic turnover rate (k(cat)) and not in the affinity for the substrate. X-ray crystallographic analysis of the ERAP2 392K allele suggests that the polymorphism interferes with the stabilization of the N terminus of the peptide both directly and indirectly through interactions with key residues participating in catalysis. This specificity switch allows the 392N allele of ERAP2 to supplement ERAP1 activity for the removal of hydrophobic N-terminal residues. Our results provide mechanistic insight to the association of this ERAP2 polymorphism with disease and support the idea that polymorphic variation in Ag processing enzymes constitutes a component of immune response variability in humans.

PubMed: 22837489
DOI: 10.4049/jimmunol.1200918

実験手法

X-RAY DIFFRACTION (3.22 Å)