IRE1alpha
中文名称
通路描述
IRE1-alpha 是一种单跨膜蛋白，位于内质网 (ER) 膜上。IRE1-alpha 的 C 端位于细胞质，N 端位于 ER 腔内。在正常细胞中，IRE1-alpha 与 BiP 形成无活性的异二聚体复合物，BiP 在 ER 腔内结合 N 端区域。当 ER 中积累未折叠蛋白时，BiP 结合未折叠蛋白，导致 IRE1-alpha:BiP 复合物解离。解离的 IRE1-alpha 形成同源二聚体。最初，lumen 侧的 N 端配对。随后发生 IRE1-alpha 在细胞质 C 端结构域的 Ser724 处的自磷酸化。磷酸化引起构象变化，使二聚体能够结合 ADP，导致进一步的构象变化，使细胞质 C 端结构域形成背对背配对。完全配对的 IRE1-alpha 同源二聚体具有内切核糖核酸酶活性，切割编码 Xbp-1 的 mRNA。释放出一个 26 个残基的多聚核糖核苷酸，并将原 Xbp-1 mRNA 的 5' 和 3' 片段重新连接。剪接后的 Xbp-1 消息编码 Xbp-1 (S)，这是一种强大的转录激活因子。Xbp-1 (S) 与 ubiquitous 转录因子 NF-Y 结合，结合编码 chaperones 的 ER 应激反应元件 (ERSE)。最新的数据表明，IRE1-alpha 同源二聚体还可以切割特定子集的信使 RNA，包括胰腺β细胞中的胰岛素 (INS) mRNA。
英文描述
IRE1alpha activates chaperones IRE1-alpha is a single-pass transmembrane protein that resides in the endoplasmic reticulum (ER) membrane. The C-terminus of IRE1-alpha is located in the cytosol; the N-terminus is located in the ER lumen. In unstressed cells IRE1-alpha exists in an inactive heterodimeric complex with BiP such that BiP in the ER lumen binds the N-terminal region of IRE1-alpha. Upon accumulation of unfolded proteins in the ER, BiP binds the unfolded protein and the IRE1-alpha:BiP complex dissociates. The dissociated IRE1-alpha then forms homodimers. Initially the luminal N-terminal regions pair. This is followed by trans-autophosphorylation of IRE1-alpha at Ser724 in the cytosolic C-terminal region. The phosphorylation causes a conformational change that allows the dimer to bind ADP, causing a further conformational change to yield back-to-back pairing of the cytosolic C-terminal regions of IRE1-alpha. The fully paired IRE1-alpha homodimer has endoribonuclease activity and cleaves the mRNA encoding Xbp-1. A 26 residue polyribonucleotide is released and the 5' and 3' fragments of the original Xbp-1 mRNA are rejoined. The spliced Xbp-1 message encodes Xbp-1 (S), a potent activator of transcription. Xbp-1 (S) together with the ubiquitous transcription factor NF-Y bind the ER Stress Responsive Element (ERSE) in a number of genes encoding chaperones. Recent data suggest that the IRE1-alpha homodimer can also cleave specific subsets of mRNAs, including the insulin (INS) mRNA in pancreatic beta cells.
所含基因
2 个基因