Introduction

Protein folding is an error-prone process, and while certain polypeptides can fold quite efficiently, a relevant fraction of other proteins fails to reach a native conformation even under normal conditions. These misfolded polypep-tides may be endowed with new and deleterious activities, act as dominant negative mutants, or may more generally get involved in spurious interactions that interfere with normal cellular functions. As such, they must be rapidly eliminated. Indeed, when the overall efficiency of protein biogenesis in a mammalian cell population was measured, it was found that up to two-thirds of newly synthesized polypeptides were rapidly destroyed (Schubert et al. 2000). In addition, cellular proteins are subjected to post-synthetic damage due to the action of reactive small molecules, proteases, and to changes in primary sequence (protein ageing). These post-synthetic changes, as well as exposure to high temperatures, can lead to a degree of protein unfolding that can be deleterious to the cell. It is therefore clear that cells must have a way to deal with this continually generated mass of aberrant and potentially damaging protein. The way the endoplasmic reticulum (ER) copes with the problem of disposing of misfolded proteins is the subject of this chapter.

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