Targeting of C-terminal (tail)-anchored proteins: Understanding how cytoplasmic activities are anchored to intracellular membranes

A class of integral membrane proteins, referred to as 'tail-anchored protei ns', are inserted into phospholipid bilayers via a single segment of hydrop hobic amino acids at the C-terminus, thereby displaying a large functional domain in the cytosol. This membrane attachment strategy allows eukaryotic cells to position a wide range of cytoplasmic activities close to the surfa ce of an intracellular membrane. Tail-anchored proteins often, but not alwa ys, demonstrate a selective distribution to specific intracellular organell es. This membrane-specific distribution is required for the large number of targeting proteins that are tail-anchored, but may or may not be critical for the numerous tail-anchored pro-apoptotic and anti-apoptotic proteins of the Bcl-2 family. Recent work has begun to address the mechanism for targe ting tail-anchored proteins to their resident membranes, but questions rema in. What targeting signals determine each protein's intracellular location? Are there receptors for these signals and, if so, how do they function? Wh at steps are required to integrate tail-anchored proteins into the phosphol ipid bilayers? In this Traffic Interchange, we summarise what is known abou t tail-anchored proteins, and outline the areas that are currently under st udy.