Ever HRD a ubiquitin-gated channel?

Abstract

Elimination of misfolded proteins of the endoplasmic reticulum (ER) requires their retrotranslocation from the ER to the cytosol via membrane-bound ubiquitin ligase complexes. Baldridge and Rapoport now reconstitute a key step of retrotranslocation, demonstrating a protein conduit gated by ubiquitination.

Figure 1

A comparison of the channel gating mechanisms for forward and retrotranslocation at the ER. Top: A model for Sec61-mediated forward translocation based on structural and biochemical studies on bacterial SecY. A monomeric Sec61 complex forms a channel that is constricted at the center by a pore ring formed by a collection of hydrophobic residues. A helix 'plug' further seals the channel from the luminal side. When a nascent polypeptide bearing a signal sequence is synthesized by the ribosome, the signal sequence is captured by the signal recognition particle (SRP), which brings the nascent chain-ribosome complex to the Sec61 channel via an ER-anchored SRP receptor. Nascent chain is inserted into the channel as a loop. The interaction of the signal sequence with the channel causes a conformational change, resulting in the removal of the 'plug' and pore opening. Bottom: Hrd1-mediated retrotranslocation for ERAD-L substrates. Hrd1 forms a homo-oligomerized pore in the ER membrane. Substrate binding to Hrd1 in the lumen causes autoubiquitination of the RING domain in the cytosol, which in turn activates the channel and allows substrate to slip through the membrane. In cells, Hrd1 is assisted by cofactors that may coordinate substrate binding with channel activation.