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4 Heat Shock Cognate Proteins and Polypeptide Translocation Across the Endoplasmic Reticulum Membrane

Jeffrey L. Brodsky, Randy Schekman


Protein translocation into the lumen of the endoplasmic reticulum (ER) is an essential step in the biogenesis of secretory proteins and of some proteins that are destined to reside in intracellular organelles. Translocation requires the hydrolysis of ATP and the function of proteins in the cytosol, in the ER membrane, and in the ER lumen (for review, see Walter and Lingappa 1986; Nunnari and Walter 1992; Rapoport 1992; Sanders and Schekman 1992). Proteins that are destined for translocation contain a signal peptide that targets the nascent chain to the cytoplasmic face of the ER membrane.

Signal peptides generally consist of a continuous stretch of nonpolar amino acids at the amino terminus of the protein (for review, see von Heijne 1990). The signal peptide is removed by signal peptidase and N-linked glycosylation may occur as the translocating polypeptide emerges in the lumen of the ER. The ER membrane is equipped with proteins that act as protein permeases or pores which facilitate the transport of the polypeptide across the ER bilayer (Simon and Blobel 1991; Görlich et al. 1992b; Müsch et al. 1992; Sanders et al. 1992). Once translocation is complete, the protein folds into its native conformation. Protein folding in the ER is aided by lumenal factors that directly catalyze folding and others that prevent unproductive folding pathways (for review, see Gething and Sambrook 1992).

Proteins are translocated across membranes in an unfolded or extended conformation (Verner and Schatz 1988; Langer and Neupert, this volume), as the various structures...

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