Quality Control Mechanisms for Protein Folding and Consequences for Failure

The proper functioning of proteins requires that they achieve a precise three-dimensional conformation. Despite the large number of conformations a protein could theoretically achieve, folding occurs with great fidelity and precision because the native state minimizes free energy. However, in a crowded cellular environment of the cell, the exposed hydrophobic regions displayed by most proteins during the folding process prevent spontaneous self-assembly. It is the chaperones that exist both in the cytosol and the endoplasmic reticulum, the locations in which protein folding occurs, that facilitate protein folding by preventing unproductive interactions between exposed hydrophobic regions, and without which nascent proteins would misfold and aggregate.;A variety of exogenous and endogenous stressors can result in an accumulation of aberrant proteins. To ameliorate these situations, the cell employs quality control mechanisms to increase the ability of the chaperone and degradation machinery to process these proteins. Despite these systems, misfolded and aggregated proteins do accumulate unchecked under certain conditions and in fact these aberrant proteins are markers of a variety of diseases.;In this work, a systems biology approach to understanding the dysfunction of cellular networks that occurs as a result of defects in protein folding and quality control mechanisms is undertaken. A mathematical model of tau pathophysiology is developed to recapitulate the behavior of healthy and aggregation-prone neurons; tau is a microtubule-associated protein that dissociates from microtubules and aggregates into paired helical filaments in the neurons of Alzheimer's disease patients. To capture the inherent variability of biological systems, two populations of neurons are developed and a sensitivity analysis is performed for each population. The unfolded protein response was directly investigated using discovery-driven methods in which high throughput microarray data is mined to elucidate the response to stress in the endoplasmic reticulum. The UPR is the means of compensating for such stress. Finally, the response of insulin resistant and insulin sensitive adipocytes will be addressed. Although insulin resistance is not typically characterized as a protein misfolding and quality control disorder, the building evidence of UPR participation in this pathological state suggests that it is indeed a member of this class of diseases.