Double J-domain piloting of an Hsp70 substrate.

Heat shock 70 kDa protein (Hsp70) chaperones play a crucial role in the biogenesis of tail-anchored proteins (TAs), starting a downstream cascade to the endoplasmic reticulum (ER) via the guided-entry-of-tail-anchored protein (GET) pathway. J-domain proteins (JDPs) are generally known to assist Hsp70s, but their specific role in TA targeting remains unclear. Cho et al. now identify two separate functions for JDPs in the process, in the initial capture of the TA and the transfer into the GET pathway. These data suggest that several Hsp70 cycles could be involved at distinct steps during protein maturation.