3D COMIC THE CHAPERONE CHAPTER 61 UPDATE

The combination of nanoscopic approaches revealed two features. Recently, advances in super-resolution imaging of live and fixed cells extended the concept of tubular and sheet-like peripheral ER domains by introducing ER matrices, densely packed ER tubular arrays, to the portfolio of ER structural domains. The latter include the nuclear envelope and the peripheral ER consisting of smooth tubular and rough sheet-like areas. The former include lipid and steroid synthesis, calcium storage, protein transport, maturation, and proteostasis some of which are assumed to occur at distinct ER subdomains ( Blobel and Dobberstein, 1975 Palade, 1975 Berridge, 2002 Brostrom and Brostrom, 2003 Clapham, 2007 Braakman and Bulleid, 2011).

Together with the size of the ER comes both an array of different functions and morphological structures. Not surprisingly, this high mobility allows the ER to be the organelle with the highest contact rate to other compartments of the endomembrane system, such as lipid droplets or mitochondria and, therefore, the nexus of inter-organelle tethering. While occupying up to a third of a cell's volume at any given time, the ER managed to “scan” and explore over 97% of a cell's volume within 15 min. Its striking dynamics were recently demonstrated via lattice light-sheet microscopy ( Valm et al., 2017). The endoplasmic reticulum (ER) represents the largest continuous tubular membrane network within nucleated mammalian cells ( Friedman and Voeltz, 2011 Figure 1).

3D COMIC THE CHAPERONE CHAPTER 61 UPDATE

Furthermore, the structural insights into the Sec61 channel are incorporated into an overview and update on Sec61 channel-related diseases-the Sec61 channelopathies-and novel therapeutic concepts for their treatment. These structural data are discussed in light of different Sec61 channel activities including ribosome receptor function, membrane insertion, and translocation of newly synthesized polypeptides as well as the putative physiological roles of the Sec61 channel as a passive ER calcium leak channel.

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

3d comic the chaperone chapter 61