The tale of tail-anchored proteins: coming from the cytosol and looking for a membrane

Abstract

A group of integral membrane proteins, known as C-tail anchored, is defined by the presence of a cytosolic NH2-terminal domain that is anchored to the phospholipid bilayer by a single segment of hydrophobic amino acids close to the COOH terminus. The mode of insertion into membranes of these proteins, many of which play key roles in fundamental intracellular processes, is obligatorily posttranslational, is highly specific, and may be subject to regulatory processes that modulate the protein's function. Although recent work has elucidated structural features in the tail region that determine selection of the correct target membrane, the molecular machinery involved in interpreting this information, and in modulating tail-anchored protein localization, has not been identified yet.

Figure 1.

Membrane insertion of tail-anchored proteins occurs after release from the ribosome. The figure illustrates the fundamental difference between the biosynthesis of a classical type II membrane protein (left) and that of a C-tail–anchored protein (right). For type II proteins, the signal anchor (red) emerges from the ribosome before termination of translation, so that it can interact with SRP (brown). For TA proteins, the hydrophobic membrane interacting sequence (red) is still sequestered within the ribosome when the stop codon is reached, so that it never becomes available to SRP.

Figure 2.

Features that determine specific targeting of tail-anchored proteins to the mitochondrial outer membrane (MOM) or ER. The cytosolic domains of the four proteins A–D are shown as a gray irregular form, whereas the the color of the COOH-terminal tail is matched to that of the corresponding target membrane. The transmembrane domain is shown as a zig-zag line. A short transmembrane domain, flanked on both sides by positively charged residues, determines targeting to the MOM (A). Loss of either of these features results in targeting to the ER (B and C). Proteins bearing tails with intermediate features (purple), i.e., a slightly lengthened hydrophobic domain and/or reduced positive charge, may be delivered to both the MOM and the ER (D). Targeting and insertion are in some cases subject to regulation (see text for details).