Structural and mechanistic understanding of Unfolded Protein Response (UPR) regulation by ER Hsp70 resident chaperone BIP.

对 ER Hsp70 常驻伴侣 BIP 调节未折叠蛋白反应 (UPR) 的结构和机制的理解。

• 批准号: MR/L007436/1
• 负责人: Maruf Ali
• 金额: $ 26.44万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL007436%2F1
• 关键词: Structural; mechanistic; understanding; Unfolded; Protein

The Eukaryotic cell has many compartments that specialises in different functions. One such compartment known as the Endoplasmic Reticulum (ER) specialises inprocessing proteins into their correct shape. In certain types of secretory cells such as antibody producing plasma cells or insulin producing beta cells the requirementto fold these extracellular proteins can increase many fold. The ER has developed a number of strategies to cope with the sudden increase in processing proteins bymaking use of a cell signalling response pathway termed the unfolded protein response, UPR. The initial activation of the UPR is thought to involve a particular region of a sensor protein known as LD. It is thought that LD interacts with a ER resident chaperone protein BIP, that helps to process secretory proteins. There are a number of models that suggest how the presence of incorrectly folded protein leads to activation of the UPR. In this proposal we aim to structurally characterise the interaction between the LD and chaperone protein BIP to understand the mechanism for activating the UPR. A failure or incorrect activation of UPR can lead to many disease states including diabetes, neurodegeneration and cancer. In cancer the solid tumour environment lacks nutrients and oxygen due to the incredible pace at which tumour grows. In order for the tumour to survive this harsh environment the UPR is switched "on". Furthermore in antibody producing plasma cells a downstream component of the UPR has been implicated in multiple myeloma and is dysregulated, therefore inhibition of UPR would help to alleviate this condition. This makes inhibition of UPR an attractive target for anticancer therapeutics.

真核细胞有许多专门负责不同功能的区室。其中一个被称为内质网（ER）的室专门负责将蛋白质加工成正确的形状。在某些类型的分泌细胞中，例如产生抗体的浆细胞或产生胰岛素的β细胞，折叠这些细胞外蛋白质的需求可能会增加许多倍。 ER 已开发出多种策略，通过利用称为未折叠蛋白反应 (UPR) 的细胞信号传导反应途径来应对加工蛋白的突然增加。 UPR 的初始激活被认为涉及称为 LD 的传感器蛋白的特定区域。人们认为 LD 与 ER 常驻伴侣蛋白 BIP 相互作用，有助于处理分泌蛋白。有许多模型表明错误折叠蛋白的存在如何导致 UPR 激活。在本提案中，我们的目标是从结构上表征 LD 和伴侣蛋白 BIP 之间的相互作用，以了解激活 UPR 的机制。 UPR 的失败或不正确激活可能导致许多疾病状态，包括糖尿病、神经退行性疾病和癌症。在癌症中，由于肿瘤生长的速度令人难以置信，实体肿瘤环境缺乏营养和氧气。为了使肿瘤能够在这种恶劣的环境中生存，UPR 被“打开”。此外，在产生抗体的浆细胞中，UPR 的下游成分与多发性骨髓瘤有关并且失调，因此抑制 UPR 将有助于缓解这种情况。这使得 UPR 的抑制成为抗癌治疗的有吸引力的目标。

项目成果

Noncanonical binding of BiP ATPase domain to Ire1 and Perk is dissociated by unfolded protein CH1 to initiate ER stress signaling.

BiP ATPase 结构域与 Ire1 和 Perk 的非典型结合被未折叠蛋白 CH1 解离，从而启动 ER 应激信号传导。

• DOI: http://dx.10.7554/elife.03522
• 发表时间: 2015
• 期刊: eLife
• 影响因子: 7.7
• 作者: Carrara M

Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer.

针对 RSK4 的重新利用的氟沙星可预防肺癌和膀胱癌的化疗耐药性和转移。

• DOI: http://dx.10.1126/scitranslmed.aba4627
• 发表时间: 2021
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Chrysostomou S

Crystal structures reveal transient PERK luminal domain tetramerization in endoplasmic reticulum stress signaling.

晶体结构揭示了内质网应激信号传导中的瞬时 PERK 管腔结构域四聚化。

• DOI: http://dx.10.15252/embj.201489183
• 发表时间: 2015
• 期刊: The EMBO journal
• 作者: Carrara M