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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response
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The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response

机译：人IRE1腔结构域的晶体结构揭示了激活未折叠蛋白反应所需的保守二聚化界面

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摘要

The unfolded protein response (UPR) is an evolutionary conserved mechanism by which all eukaryotic cells adapt to the accumulation of unfolded proteins in the endoplasmic reticulum (ER). Inositol-requiring kinase 1 (IRE1) and PKR-related ER kinase (PERK) are two type Ⅰ transmembrane ER-localized protein kinase receptors that signal the UPR through a process that involves homodimerization and autophosphorylation. To elucidate the molecular basis of the ER transmembrane signaling event, we determined the x-ray crystal structure of the luminal domain of human IRE1α. The monomer of the luminal domain comprises a unique fold of a triangular assembly of β-sheet clusters. Structural analysis identified an extensive dimerization interface stabilized by hydrogen bonds and hydrophobic interactions. Dimerization creates an MHC-like groove at the interface. However, because this groove is too narrow for peptide binding and the purified luminal domain forms high-affinity dimers in vitro, peptide binding to this groove is not required for dimerization. Consistent with our structural observations, mutations that disrupt the dimerization interface produced IRE1α molecules that failed to either dimerize or activate the UPR upon ER stress. In addition, mutations in a structurally homologous region within PERK also prevented dimerization. Our structural, biochemical, and functional studies in vivo altogether demonstrate that IRE1 and PERK have conserved a common molecular interface necessary and sufficient for dimerization and UPR signaling.
机译：未折叠蛋白反应（UPR）是一种进化保守的机制，所有真核细胞都通过这种机制适应内质网（ER）中未折叠蛋白的积累。需要肌醇的激酶1（IRE1）和与PKR相关的ER激酶（PERK）是两种Ⅰ型跨膜ER定位蛋白激酶受体，通过涉及同二聚化和自磷酸化的过程向UPR发出信号。为了阐明ER跨膜信号转导事件的分子基础，我们确定了人IRE1α的腔结构域的X射线晶体结构。腔结构域的单体包括β-片簇的三角形组装的独特折叠。结构分析确定了由氢键和疏水相互作用稳定的广泛的二聚界面。二聚化在界面处产生类似MHC的凹槽。但是，由于该槽对于肽结合而言太窄，并且纯化的腔结构域在体外形成高亲和力的二聚体，因此二聚化不需要肽与该槽结合。与我们的结构观察结果一致，破坏二聚化界面的突变产生了IRE1α分子，该分子不能在ER应激下二聚化或激活UPR。此外，PERK中结构同源区域的突变也阻止了二聚化。我们在体内的结构，生化和功能研究总共表明IRE1和PERK保留了二聚化和UPR信号转导所必需和足够的共同分子界面。

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