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The insertion mechanism for tail-anchored proteins. (A) In this post-translational pathway for the insertion of tail-anchored membrane proteins into the ER, a soluble pre-targeting complex captures the hydrophobic C-terminal transmembrane segment (red) after it emerges from the ribosomal exit tunnel and loads it onto the Get3 targeting factor. The resulting complex is targeted to the ER membrane by interaction with the Get1–Get2 receptor complex, which functions as a membrane protein insertion machine. After the tail-anchored protein is released from Get3 and inserted into the ER membrane, Get3 is recycled back to the cytosol. This targeting cycle is conceptually similar to protein targeting by SRP (see Figure 12–20). Although not shown in the figures, both Get3 and SRP bind and hydrolyze nucleoside triphosphates to provide directionality to the targeting cycle. ATP is used by Get3, and GTP is used by SRP. (B) Crystal structure of the Get3 targeting factor bound to a transmembrane segment (red helix). The hydrophobic transmembrane segment binds to a deep groove in Get3 lined by hydrophobic amino acids (yellow), including many flexible methionines. (PDB code: 4XTR.)