Enhanced Chaperone Clustering Facilitates Protein Folding in the Endoplasmic Reticulum of Yeast

Abstract

The chaperone BiP plays several roles in the endoplasmic reticulum (ER): translocation, protein folding, ER-associated degradation, and a modulating function in Ire1p-regulated ER stress. Experimental evidence has suggested the existence of BiP heterogeneity in the ER. A cooperative mechanism known as entropic pulling has been proposed to explain how the molecular interaction of multiple BiP molecules on unfolded proteins occurs. We have developed a model to explore the potential advantages of the binding of multiple BiP molecules in the facilitation of protein folding in the ER to explain the heterogeneity, and take advantage of entropic pulling.Simulation scenarios were enacted to gauge the effectiveness of multiple chaperone binding in protein folding. Using two metrics: folding efficiency and chaperone cost, we determined that the single binding site model had a higher efficiency than multiple binding models, in the absence of cooperativity. Through entropic pulling, however, multiple chaperones do work in concert to facilitate the resolubilization and ultimate yield of folded proteins. Under a cooperative scenario, multiple binding models used fewer chaperones and enjoyed a higher folding efficiency than the single binding site model.In conclusion, our in-silico experiments reveal that clusters of BiP molecules bound to unfolded proteins could enhance folding efficiency through cooperative action via entropic pulling.