Location: Fields Institute , 222 College Street, Toronto

***POSTPONED FROM NOV 20 TO FEB 19***
February 19, 2010- 3:30 p.m.
Dr. Santiago Schnell
University of Michigan

How is protein load sensed in the endoplasmic reticulum?

One of the main functions of the endoplasmic reticulum (ER) is to serve as the cell protein-folding factory. The ER is responsible for the synthesis, folding, assembly and modification of one third of the eukaryotic proteome. Proteins enter the ER as unfolded polypeptide chains with variable fluxes depending on the physiological state of the cell. A sudden increase in the demand for a protein or the disruption of a folding reaction causes an imbalance between protein-folding load and capacity of the ER, which can lead to the accumulation of unfolded protein in the ER lumen. The ER protein balance is regulated by several signaling pathways, which are collectedly termed the unfolded protein response. The unfolded protein response is activated by three transducers, which are enzymes whose oligomerization-induced activation is linked to perturbed protein folding in the ER. Three model mechanisms have been proposed for how these enzymes sense the unfolded protein load in the ER lumen: (i) direct recognition model, (ii) indirect recognition model and (iii) hybrid recognition model. We developed mathematical formulations for these mechanisms. We found that our formulations of both directed and indirect recognition models have serious discrepancies with the experimental data. However, our formulation of hybrid recognition model tests against most experimental results. We suggest a set of experiments that have not been yet carried out to test our model mechanism of protein load sensing in the ER lumen. Our new model also provides new insights into the mechanisms of protein homeostasis in the ER.

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