A chaperone triad in the GET pathway
How newly synthesized membrane proteins are escorted to the correct membrane destination is a fundamental mechanistic challenge. In the Guided Entry of Tail-anchored protein (GET) pathway, newly synthesized tail-anchored proteins (TAs) proteins are delivered to the ER via multiple energetically downhill relays across a chaperone triad, which begins with Hsp70 and ends on the targeting factor Get3. The GET pathway provides an excellent system to explore how a multi-component chaperone network protects and funnels nascent membrane proteins in the cell to safeguard their biogenesis, and how membrane proteins with degenerate targeting signals are triaged by these chaperones to impart organelle specificity of their localization.
An Hsp70-cochaperone cascade mediates TA targeting to the ER in the GET pathway. TAs released from the ribosome are captured and solubilized by cytosolic Hsp70 with help of Hsp40 cochaperones (step 1). Ssa1 associates with the cochaperone Sgt2 via its C-terminal EEVD motif, forming the first transfer complex in which TA is loaded onto Sgt2 (step 2). Get4/5 bridges between Sgt2 and the targeting factor Get3, forming the second transfer complex in which TA is relayed onto Get3 (step 3). TA loading activates ATP hydrolysis on Get3, which drives its dissociation from Get4/5 and commits it to deliver the TA to the Get1/2 receptor complex at the ER membrane (step 5). Available structural information on the TA transfer complexes in this pathway are summarized in the lower panel.