Protein folding in the ER

The endoplasmic reticulum (ER) is a major protein folding compartment for s ecreted, plasma membrane and organelle proteins. Each of these newly-synthe sized polypeptides folds in a deterministic process, affected Ey the unique conditions that exist in the ER. An understanding of protein folding in th e ER is a fundamental biomolecular challenge at two levels. The first level addresses how the amino acid sequence programs that polypeptide to efficie ntly arrive at a particular fold Out Of a multitude of alternatives, and ho w different sequences obtain similar folds. At the second level are the iss ues introduced by folding not in the cytosol, but in the ER, including the risk of aggregation in a molecularly crowded environment, accommodation of post-translational modifications and the compatibility with subsequent intr acellular trafficking. This review discusses both the physicochemical and c ell biological constraints of folding, which are the challenges that the ER molecular chaperones help overcome.