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

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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.