The Get3-receptor complex in tail-anchored membrane protein targeting

For targeting and insertion of proteins to the endoplasmic reticulum (ER) membrane different pathways are utilized. Proteins carrying a N-terminal signal sequence are targeted by the signal recognition particle (SRP)-dependent pathway. In contrast to this well characterized pathway, TA-proteins (TA) are excluded from co-translational targeting by position of their C-terminal hydrophobic signal sequence, which anchors them to the membrane. TA-proteins play important roles in protein translocation, membrane fusion and apoptosis. They are post-translationally delivered to the ER by the Get3 ATPase interacting with the hetero-oligomeric Get1/2 receptor. We have determined crystal structures of the Get3 ATPase in different nucleotide loaded states as well as Get3/receptor complexes. These structural snapshots are complemented by biochemical and biophysical experiments and are integrated into a structure based cycle of TA membrane protein biogenesis.