Membrane Protein Targeting to the Endoplasmic Reticulum

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Most integral proteins are embedded in membranes by hydrophobic, alpha helical sequences (~20 amino acids longa called transmembrane domains (TMDs). Eukaryotic cells have a variety of mechanisms that shield TMDs from the moment they emerge out of the ribosome until they are stably inserted into the target organelle. When normal protein targeting is disrupted, membrane proteins can form cytosolic protein aggregates, become targeted to incorrect membranes, or be prematurely destroyed by the proteasome. For most membrane proteins in the secretory pathway, exposure of TMDs to the cytosol is minimized by a mechanism that physically couples protein synthesis to insertion into the endoplasmic reticulum (ER) membrane [1] (Figure 1). This is achieved by co-translational recognition of a hydrophobic sequence on the substrate (either a cleavable signal sequence or the first TMD)  by the signal recognition particle (SRP), which is docked near the nascent chain exit tunnel on the ribosome. Signal sequence binding to the SRP causes translational pausing and enhances recruitment to the SRP receptor in the ER membrane. The ribosome and signal sequence are then transferred to the Sec61 channel, protein synthesis resumes, and nascent chains translocate into the ER lumen while allowing TMDs to partition into the lipid bilayer through a lateral gate.

Approximately 5% of membrane proteins in the secretory pathway have a single TMD near the C terminus, which also serves as an ER membrane signal sequence. These tail-anchored (TA) proteins are functionally diverse and many are essential. For example, a large fraction of SNAREs (soluble NSF attachment protein receptors, which are proteins that mediate vesicle fusion) are tail-anchored. Historically, a key operational problem of TA protein biogenesis was defined by the discovery of a protein-assisted mechanism that can post-translationally insert TA proteins into the ER membrane independently of Sec61 [2]. After the identification of a TA protein targeting factor [4,5], a flurry of complementary genetic, biochemical, and structural studies have in a short time identified most, if not all, of the components for a novel protein targeting pathway [6,7]. This review presents my synthetic view of the conserved GET pathway in yeast and mammalian cells (Figure 1) with emphasis on fundamental mechanistic insights of general relevance to membrane protein targeting and discusses the critical unanswered questions in the field.