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.
Highlights
The endoplasmic reticulum (ER) represents the largest continuous tubular membrane network within nucleated mammalian cells (Friedman and Voeltz, 2011; Figure 1)
Based on our observations on the Ca2+ permeability of the open Sec61 channel and its limitation by BiP, we propose that the above-described regulatory circuit for maintenance of ATP supply of the human ER involves the Sec61 channel in the ER membrane and the ER lumenal BiP
The mammalian Sec61 complex forms a dynamic and precursor gated channel, which can provide an aqueous path for polypeptides into the ER lumen and is regulated by various allosteric effectors
Summary
The endoplasmic reticulum (ER) represents the largest continuous tubular membrane network within nucleated mammalian cells (Friedman and Voeltz, 2011; Figure 1). Together with the size of the ER comes both an array of different functions and morphological structures The former include lipid and steroid synthesis, calcium storage, protein transport, maturation, Sec61-Channel and Channelopathies 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). BiP and TRAP can bind to precursor polypeptides in transit through the Sec channel and support their partial or complete translocation by acting as molecular ratchets This capacity was directly demonstrated for BiP by reconstitution of transport components, originally present in an ER-derived detergent extract, into proteoliposomes and their subsequent use in cellfree transport assays. #Bag complex - TRC35 - Ubl4A - Bag (Bat3) SGTA TRC40 (Asna-1) TA receptor - CAML
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