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April 17th, 2025
Version: 2
University of Cambridge
biochemistry
biorxiv

A structural basis for chaperone repression of stress signalling from the endoplasmic reticulum

Neidhardt, L.Open in Google Scholar•Tung, J.Open in Google Scholar•Kuchersky, M.Open in Google Scholar•Milczarek, J.Open in Google Scholar•Kargas, V.Open in Google Scholar•Stott, K.Open in Google Scholar•Rosenzweig, R.Open in Google Scholar•Ron, D.Open in Google Scholar•Yan, Y.Open in Google Scholar

The endoplasmic reticulum (ER) unfolded protein response (UPR) is tuned by the balance between unfolded proteins and chaperones. While reserve chaperones are known to suppress the UPR transducers via their stress-sensing luminal domains, the underlying structural mechanisms remain unclear. Cellular and biophysical analyses established that the ER chaperone AGR2 forms a repressive complex with the luminal domain of the UPR transducer IRE1{beta}. Structural prediction, X-ray crystallography and NMR spectroscopy identify critical interactions between an AGR2 monomer and a regulatory loop in IRE1{beta}s luminal domain.

However, in the repressive complex it is an AGR2 dimer that binds IRE1{beta}. Cryo-EM reconstruction reveals a mechanism of unanticipated simplicity: one AGR2 protomer engages the regulatory loop, while the second asymmetrically binds IRE1{beta}s luminal domains C-terminus, blocking IRE1{beta}-activating dimerization.

Molecular dynamic simulations indicate that the second, disruptive AGR2 protomer exploits rare fluctuations in the IRE1{beta} dimer that expose its binding site. Thus, AGR2 actively disrupts IRE1{beta} dimers to suppress the UPR, while chaperone clients compete for AGR2 to trigger UPR signalling

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