Recently, cryoelectron tomography of translocons in native ER membrane vesicles, derived from human cell lines or patient fibroblasts, and even intact cells has given unprecedented insights into the architecture and dynamics of the native translocon and the Sec61 channel. This ensemble of proteins facilitates ER targeting of precursor polypeptides, modification of precursor polypeptides in transit through the Sec61 complex, and Sec61 channel gating, i.e., dynamic regulation of the pore forming subunit to mediate precursor transport and calcium efflux.

The translocon comprises the polypeptide-conducting Sec61 channel and several additional proteins and complexes that are permanently or transiently associated with the heterotrimeric Sec61 complex. The membrane of the endoplasmic reticulum (ER) of nucleated human cells harbors the protein translocon, which facilitates membrane integration or translocation of almost every newly synthesized polypeptide targeted to organelles of the endo- and exocytotic pathway. 5Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, Netherlands.4Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany.3Center for Bioinformatics, Saarland University, Saarbrücken, Germany.2Department of Molecular Structural Biology, Max-Planck Institute of Biochemistry, Martinsried, Germany.1Competence Center for Molecular Medicine, Saarland University Medical School, Homburg, Germany.Sven Lang 1 * Stefan Pfeffer 2 Po-Hsien Lee 3 Adolfo Cavalié 4 Volkhard Helms 3 Friedrich Förster 5 Richard Zimmermann 1

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