![]() ![]() Eukaryotic SRP is a multi-subunit ribonucleoprotein complex, which binds to translating ribosomes exposing nascent SRP recognition sequences comprising N-terminal signal sequences and signal anchor (SA) sequences. ![]() Many ER membrane proteins are targeted cotranslationally with the assistance of the highly conserved signal recognition particle (SRP) 1– 5. In the case of ER-targeted proteins, aggregation is prevented by sophisticated machineries, which selectively recognize and shield TM domains in the cytosol 1– 5. A general challenge during the targeting of membrane proteins is aggregation of hydrophobic transmembrane (TM) domains prior to insertion into the lipid bilayer. Integral membrane proteins that follow the secretory and endocytic pathways are synthesized on cytosolic ribosomes and targeted to the membrane of the endoplasmic reticulum (ER). ![]() In this way, the position of a transmembrane domain within nascent ER-targeted proteins mediates partitioning into either the GET or SRP pathway directly at the ribosomal tunnel exit. Exposure of internal transmembrane domains at the tunnel exit induces high-affinity ribosome binding of SRP, which in turn prevents ribosome binding of Get4/5. The contact sites of Get4/5 on the ribosome overlap with those of SRP, the factor mediating cotranslational ER-targeting. Get4/5 binds directly and with high affinity to ribosomes, positions Sgt2 close to the ribosomal tunnel exit, and facilitates the capture of tail-anchored proteins by Sgt2. Here we uncover how the yeast GET pathway component Get4/5 facilitates capture of tail-anchored proteins by Sgt2, which interacts with tail-anchors and hands them over to the targeting component Get3. The guided entry of tail-anchored proteins (GET) pathway assists in the posttranslational delivery of tail-anchored proteins, containing a single C-terminal transmembrane domain, to the ER.
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