The endoplasmic reticulum (ER) serves as the site of synthesis and maturation of soluble and membrane-bound proteins destined for secretion and for other compartments in the cell. Their transport from the ER is highly regulated: Misfolded proteins, incompletely folded proteins, unassembled subunits, and partially oligomerized proteins are, as a rule, retained and degraded. This """"""""quality control"""""""" secures the functionality of the proteins that are deployed, and provides the cell with an important mechanism for post-translational control of protein expression. Our overall goal is to characterize the underlying principles of this important phenomenon at a cell biological and molecular level.
Our specific aims are: 1) to determine the role of BiP/GRP78 in the selective transport of proteins from the ER to the Golgi complex; 2) to identify and analyze, using novel protein cross-linking techniques, other cellular proteins that associate with newly synthesized and misfolded proteins in the ER, in the intermediate compartment and the cis Golgi network. these are the organelles most intimately involved in quality control; 3) to isolate and characterize the intermediate compartment which serves as a port of exit from the ER and a potential site for protein assembly and sorting; 4) to analyze the retrograde transport of proteins from the intermediate compartment and the cis Golgi compartment in as much as it may be responsible for retrieving misfolded proteins to the ER; 5) to investigate the role of medial and trans Golgi elements as potential sites for further quality control. The experiments will be performed in tissue culture cells and S. cerevisiae. The model proteins include viral spike glycoproteins and endogenous yeast proteins. It is hoped that these studies will enhance our general understanding of the reactions involved phenomena such as cell surface expression of receptors and growth factor secretion and other ER functions with a central role in inter-cellular communication and malignant transformation.
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