Biogenesis of tail-anchored proteins: the beginning for the end?

Abstract

Tail-anchored proteins are a distinct class of integral membrane proteins located in several eukaryotic organelles, where they perform a diverse range of functions. These proteins have in common the C-terminal location of their transmembrane anchor and the resulting post-translational nature of their membrane insertion, which, unlike the co-translational membrane insertion of most other proteins, is not coupled to ongoing protein synthesis. The study of tail-anchored proteins has provided a paradigm for understanding the components and pathways that mediate post-translational biogenesis of membrane proteins at the endoplasmic reticulum. In this Commentary, we review recent studies that have converged at a consensus regarding the molecular mechanisms that underlie this process – namely, that multiple pathways underlie the biogenesis of tail-anchored proteins at the endoplasmic reticulum.

Protein Folding and Quality Control in the ER

“…1B) (Rabu et al 2009;Brodsky 2010;Borgese and Fasana 2011). Tail-anchored (TA) proteins are translated in the cytosol, and the carboxy-terminal single trans-membrane domain (TMD) is recognized by the cytoplasmic chaperones TRC40 (Get3) together with the three-protein complex The ER signal sequence of a newly synthesized polypeptide is bound by a signal-recognition particle (SRP).…”

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).…”

“…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).…”

Crystal Structure of Get4-Get5 Complex and Its Interactions with Sgt2, Get3, and Ydj1

“…Interestingly, the genes showing co-sensitivity with MDY2 and YOR164C are quite similar and include GET3. In S. cerevisiae, GET complexes, including Get1-Get2 and Get3, take part in the insertion of a subset of tail-anchored (TA) proteins into the ER membrane (11,12). These TA proteins insert into the membrane using a single transmembrane segment in the C-terminal region, leaving the N-terminal functional domain in the cytosol.…”