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.

Fig. 1.

Theoretical general scheme for the post-translational targeting and insertion of tail-anchored membrane proteins at the ER. The protein precursor is recognised by cytosolic factors as the TM segment folds inside the ribosome, or just after it emerges from the exit tunnel, thus forming a TM-segment recognition complex (1). At the ER membrane, this complex either directly supports unassisted partitioning into the membrane (2), docks with a receptor (3) or hands the substrate to a dedicated integrase (4). Alternatively, after docking with the receptor (3), the tail-anchored protein might then either undergo unassisted partitioning (5) or be passed on to the integrase (6).

Fig. 2.

SRP-dependent pathway for biogenesis of tail-anchored proteins at the ER. The interaction of the SRP-tail-anchored protein complex with the ER-localised SRP receptor most probably depends on both components being in the GTP-bound form. The SRP receptor is normally associated with the Sec61 complex, raising the possibility that tail-anchored proteins that utilise the SRP pathway might be integrated via this well-characterised ER translocon (Cross et al., 2009). Alternatively, the nascent chain could simply freely partition into the lipid bilayer after docking at the SRP receptor. In this model, the role of GTP hydrolysis is to facilitate the disassembly of the SRP–SRP-receptor complex to enable further rounds of SRP-dependent targeting to the ER (Cross et al., 2009).

Fig. 3.

Hsp40-Hsc70-dependent pathway for the biogenesis of tail-anchored proteins at the ER. General chaperones of the heat-shock family can accept and shield tail-anchored proteins with a TM segment of relatively low hydrophobicity (Rabu et al., 2008), presumably preventing their aggregation. This interaction might simply enable the subsequent unassisted integration of the TM segment by direct partitioning into the lipid bilayer, or allow a similar process for which a dedicated ER-membrane receptor is a prerequisite. No such receptor has been identified to date and, similarly, any role for an integrase during the Hsp40-Hsc70 pathway for biogenesis of tail-anchored proteins remains hypothetical.

Fig. 4.

GET pathway for the biogenesis of tail-anchored proteins at the yeast ER. Get3 is part of a TM segment recognition complex that contains Get4 and Get5 (Jonikas et al., 2009; Schuldiner et al., 2008) and that is most probably conserved in higher eukaryotes (Stefanovic and Hegde, 2007; Favaloro et al., 2008). The integral membrane proteins Get1 and Get2 form a hetero-oligomeric receptor at the ER membrane that binds to Get3 bound to a tail-anchored protein (Auld et al., 2006; Schuldiner et al., 2005; Schuldiner et al., 2008). Whether the subsequent integration of tail-anchored proteins into the lipid bilayer occurs by direct partitioning or via an integrase is currently unknown.