Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming
Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming
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DOI：
10.1073/pnas.1101262108
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发表时间：
2011-05-10
影响因子：
11.1
通讯作者：
Oppermann, Udo
中科院分区：
文献类型：
--
作者：
Kochan, Grazyna;Krojer, Tobias;Oppermann, Udo
内质网氨肽酶 1 (ERAP1) 是一种多功能酶，参与将肽修剪至最佳长度，以便由主要组织相容性复合体 (MHC) I 类分子呈递。 ERAP1 的多态性与慢性炎症性疾病有关，包括强直性脊柱炎 (AS) 和牛皮癣，随后的体外酶研究表明 ERAP1 变体具有独特的催化特性。为了了解这种酶的结构-活性关系，我们确定了人类 ERAP1 在开放和闭合状态下的晶体结构，这提供了催化路径上的第一个快照。 ERAP1 是一种锌金属肽酶，具有典型的 H-E-X-X-H-(X)(18)-E 锌结合和 G-A-M-E-N 基序，是胶津星蛋白酶家族成员的特征。这些结构揭示了广泛的域运动，包括活性位点闭合以及三种不同的开放构象，从而提供了对催化循环的见解。 GWAS 研究中与 AS 密切相关的 K(528)R 突变体显示肽加工特性显着改变，这可能与域间相互作用受损有关。
Endoplasmatic reticulum aminopeptidase 1 (ERAP1) is a multifunctional enzyme involved in trimming of peptides to an optimal length for presentation by major histocompatibility complex (MHC) class I molecules. Polymorphisms in ERAP1 have been associated with chronic inflammatory diseases, including ankylosing spondylitis (AS) and psoriasis, and subsequent in vitro enzyme studies suggest distinct catalytic properties of ERAP1 variants. To understand structure-activity relationships of this enzyme we determined crystal structures in open and closed states of human ERAP1, which provide the first snapshots along a catalytic path. ERAP1 is a zinc-metallopeptidase with typical H-E-X-X-H-(X)(18)-E zinc binding and G-A-M-E-N motifs characteristic for members of the gluzincin protease family. The structures reveal extensive domain movements, including an active site closure as well as three different open conformations, thus providing insights into the catalytic cycle. A K(528)R mutant strongly associated with AS in GWAS studies shows significantly altered peptide processing characteristics, which are possibly related to impaired interdomain interactions.