5 Structure, Function, and Regulation of the Endoplasmic Reticulum Chaperone, BiP

Abstract

I. INTRODUCTION
Within the lumen of the endoplasmic reticulum (ER), a variety of resident ER proteins assist newly translocated nascent polypeptides to fold into their correct tertiary and quaternary structures. These resident proteins include both molecular chaperones that recognize and stabilize partially folded intermediates during polypeptide folding and assembly and enzymes that catalyze rate-determining steps in folding, such as protein disulfide isomerase and peptidyl prolyl isomerases (for review, see Gething and Sambrook 1992). Prominent among the molecular chaperones, both in its relative abundance in the ER lumen and as a focus of recent experimental attention, is BiP, the sole ER-located member of the stress-70 (hsp70) protein family. In mammalian cells, this protein was originally described independently as the immunoglobulin heavy-chain binding protein, found in noncovalent association with heavy chains in myeloma cells that do not synthesize immunoglobulin light chains (Haas and Wabl 1983), and as the glucose-regulated protein, Grp78 (Pouyssegur et al. 1977), one of a set of highly abundant ER proteins whose rate of synthesis is increased by glucose starvation or a variety of other cellular stress conditions (Lee 1987), In Saccharomyces cerevisiae, BiP is the product of the KAR2 gene (Normington et al. 1989; Rose et al. 1989; Nicholson et al. 1990), one of a class of genes originally defined as being involved in nuclear fusion following mating of yeast cells (Polaina and Conde 1982). BiP is now known to associate transiently with a wide variety of newly synthesized wild-type exocytotic proteins and more permanently with malfolded or...