Membrane Protein Insertion at the Endoplasmic Reticulum

Abstract

Integral membrane proteins of the cell surface and most intracellular compartments of eukaryotic cells are assembled at the endoplasmic reticulum. Two highly conserved and parallel pathways mediate membrane protein targeting to and insertion into this organelle. The classical cotranslational pathway, utilized by most membrane proteins, involves targeting by the signal recognition particle followed by insertion via the Sec61 translocon. A more specialized posttranslational pathway, employed by many tail-anchored membrane proteins, is composed of entirely different factors centered around a cytosolic ATPase termed TRC40 or Get3. Both of these pathways overcome the same biophysical challenges of ferrying hydrophobic cargo through an aqueous milieu, selectively delivering it to one among several intracellular membranes and asymmetrically integrating its transmembrane domain(s) into the lipid bilayer. Here, we review the conceptual and mechanistic themes underlying these core membrane protein insertion pathways, the complexities that challenge our understanding, and future directions to over-come these obstacles.

SGTA antagonizes BAG6-mediated protein triage

“…A similar pathway for tail-anchored protein biogenesis is found in Saccharomyces cerevisiae, where the TRC40 homolog Get3 mediates delivery to the endoplasmic reticulum (1,12). An upstream loading complex is also present, although in this case it is composed of Get4 (equivalent to TRC35), Get5 (equivalent to UBL4A), and small glutamine-rich tetratricopeptide repeat-containing protein 2 (Sgt2), but with no obvious equivalent of the BAG6 protein involved (1,12,13). Strikingly, a mammalian ortholog of Sgt2, SGTA (small glutamine-rich tetratricopeptide repeat-containing protein α), is a known interacting partner of BAG6 (14) that has been shown to associate with both tail-anchored proteins and a range of other hydrophobic polypeptides (9,(15)(16)(17).…”

“…Tail-anchored protein substrates are subsequently handed on to a second component, TRC40, which mediates their ATP-dependent delivery to the endoplasmic reticulum membrane (1,11,12). A similar pathway for tail-anchored protein biogenesis is found in Saccharomyces cerevisiae, where the TRC40 homolog Get3 mediates delivery to the endoplasmic reticulum (1,12). An upstream loading complex is also present, although in this case it is composed of Get4 (equivalent to TRC35), Get5 (equivalent to UBL4A), and small glutamine-rich tetratricopeptide repeat-containing protein 2 (Sgt2), but with no obvious equivalent of the BAG6 protein involved (1,12,13).…”

“…membrane protein targeting | protein homeostasis P rotein targeting to the endoplasmic reticulum can be either coor posttranslational and involves the binding of a hydrophobic signal sequence by delivery factors such as signal recognition particle or components of the TRC/GET pathway, respectively (1). Inefficient recognition and/or delivery of precursor proteins destined for the endoplasmic reticulum can lead to their cytosolic accumulation, resulting in toxicity such as that observed in neurodegenerative disorders such as prionopathies (2,3).…”

“…In this case, the BAG6 complex functions as an upstream loading factor that binds the hydrophobic transmembrane spanning regions of newly synthesized tail-anchored proteins shortly after their synthesis (11). Tail-anchored protein substrates are subsequently handed on to a second component, TRC40, which mediates their ATP-dependent delivery to the endoplasmic reticulum membrane (1,11,12). A similar pathway for tail-anchored protein biogenesis is found in Saccharomyces cerevisiae, where the TRC40 homolog Get3 mediates delivery to the endoplasmic reticulum (1,12).…”

Stitching proteins into membranes, not sew simple

“…Furthermore accessory proteins in addition to core translocon components are likely to have substrate specific roles in membrane protein assembly, especially in the case of TRAM (translocating chain-associating membrane protein), which has been suggested to play a chaperoning role in this process by collecting poorly hydrophobic TM segments at a precise location within or adjacent to the translocon (Tamborero et al, 2011). We have not touched on the potential functions of other translocon accessory membrane proteins such as Sec62/Sec63 or TRAP, in complementing the role of the translocon in membrane protein insertion and folding (Shao and Hegde, 2011).…”