The endoplasmic reticulum (ER) is an organelle most often associated with protein folding, translocation, degradation, and protein maturation. The chaperone protein BiP is a resident protein of the ER in budding yeast (S. cerevisiae); it returns the cell to homeostasis following stress such as heat, lack of nutrients, or an imbalance in pH. ER stress leads proteins to unfold or misfold and aggregate, a toxic phenomenon that is implicated in such diseases such as Alzheimer's and Parkinson's.

In order to explore BiP's roles in the ER, we have developed a spatial model of translocation, in which BiP transports nascent proteins through the ER membrane into the aqueous ER lumen, with the assistance of the co-chaperone Sec63. When Sec63 is on the membrane, it recruits BiP and facilitates translocation. Thus spatial localization and function are linked at the ER membrane, and the distribution of BiP is heterogeneous in the ER.

We have used fluorescence data, captured by collaborator Carissa Young, to determine the molecular heterogeneity of BiP. Employing a method called Number and Brightness (N&B), we determined the degree of BiP clustering on unfolded proteins. Stress was induced on one group of cells, while the control cells were not stressed. We found that in the stressed case, BiP molecules were clustered to a much larger extent than in the unstressed case. To better understand the potential advantages of BiP clustering, we have created a model that encompasses the functions of BiP in the ER. We found that the clustering facilitated increased protein folding efficiency as well as decreased utilization of chaperones.