An Update on Sec61 Channel Functions, Mechanisms, and Related Diseases

Abstract

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. 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. 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. 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. 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. 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.

ER import of small human presecretory proteins: components and mechanisms

“…, Table ) . Today these components represent one of several ER‐targeting pathways for precursor polypeptides, which in this case operates cotranslationally . Notably, however, SRP and SR can also act post‐translationally, as has been observed for TA membrane proteins .…”

“…Thus, transport into the ER either implies the complex insertion of membrane proteins into the ER membrane or the import of soluble proteins into the ER lumen. Information for both, ER transport and ER targeting is encoded by specific signals or zip codes in the respective precursor polypeptides and, subsequently, decoded by various transport components present in the cytosol, the ER membrane, and the ER lumen (in more detail reviewed in ). In the case of various types of membrane proteins – except for tail‐anchored (TA) ones – the initial insertion into the polypeptide‐conducting channel is followed by integration into the ER membrane.…”

“…N‐terminal signal peptides have a tripartite structure with a positively charged N‐region, a central H‐region, and a slightly polar C‐region . With the exception of ER‐resident proteins, for all proteins passing quality control, their transport into the ER is followed by vesicular transport to the functional intra‐ or extracellular location .…”

The signal peptide as a new target for drug design

“…Most cell-surface and secreted human proteins, produced by more than 40% of the~20,000 protein-encoding genes, 6 are transported to the cell membrane by the Sec61 secretory pathway, [7][8][9][10][11][12][13][14][15] which is highly conserved in eukaryotes, all the way back the evolutionary chain to bacteria. [7][8][9] Such proteins in humans are translated by ribosomes on the surface of the ER, then transported to the cell membrane via the Golgi apparatus.…”

“…16 Successful translocation of these proteins is important for proper function of cells and defects in protein translocation have been linked to many diseases, including cancer and numerous hereditary diseases. 14,17 Drugs targeting the nascent protein chain during co-translational translocation can potentially reduce expression of many cell-surface and secretory proteins that are important therapeutic targets, such as type I and type II transmembrane receptors, G-protein coupled receptors (GCPRs), inflammatory cytokines, etc. In addition to drugs for treating human conditions arising from protein overexpression or malfunction, there are potential opportunities for new anti-infective drugs.…”