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

真核细胞有许多区室，专门从事不同的功能。其中一个被称为内质网（ER）的隔室专门将蛋白质加工成正确的形状。在某些类型的分泌细胞中，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的需要可以增加许多倍。ER已经开发了许多策略来科普处理蛋白质的突然增加，通过利用称为未折叠蛋白质反应（UPR）的细胞信号传导反应途径。UPR的初始激活被认为涉及称为LD的传感蛋白的特定区域。据认为LD与ER驻留伴侣蛋白BIP相互作用，其有助于加工分泌蛋白。有许多模型表明错误折叠的蛋白质的存在如何导致UPR的激活。在这个提议中，我们的目标是从结构上阐明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导致许多疾病状态，包括糖尿病、神经变性和癌症。在癌症中，由于肿瘤生长的惊人速度，实体瘤环境缺乏营养和氧气。为了让肿瘤在这种恶劣的环境中生存下来，普遍定期审议被“打开”。此外，在产生抗体的浆细胞中，UPR的下游组分与多发性骨髓瘤有关，并且是失调的，因此抑制UPR将有助于缓解这种状况。这使得UPR的抑制成为抗癌治疗的有吸引力的靶标。

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.