Abstract:
:In endoplasmic reticulum-associated protein degradation (ERAD), membrane proteins are ubiquitinated, extracted from the membrane, and degraded by the proteasome. The cytosolic ATPase Cdc48 drives extraction by pulling on polyubiquitinated substrates. How hydrophobic transmembrane (TM) segments are moved from the phospholipid bilayer into cytosol, often together with hydrophilic and folded ER luminal protein parts, is not known. Using a reconstituted system with purified proteins from Saccharomyces cerevisiae, we show that the ubiquitin ligase Doa10 (Teb-4/MARCH6 in animals) is a retrotranslocase that facilitates membrane protein extraction. A substrate's TM segment interacts with the membrane-embedded domain of Doa10 and then passively moves into the aqueous phase. Luminal substrate segments cross the membrane in an unfolded state. Their unfolding occurs on the luminal side of the membrane by cytoplasmic Cdc48 action. Our results reveal how a membrane-bound retrotranslocase cooperates with the Cdc48 ATPase in membrane protein extraction. :The inside of a cell contains many different compartments called organelles, which are separated by membranes. Each organelle is composed of a unique set of proteins and performs specific roles in the cell. The endoplasmic reticulum, or ER for short, is an organelle where many proteins are produced. Most of these proteins are then released from the cell or sorted to other organelles. The ER has a strict quality control system that ensures any faulty proteins are quickly marked for the cell to destroy. However, the destruction process itself does not happen in the ER, so faulty proteins first need to leave this organelle. This is achieved by a group of proteins known as endoplasmic reticulum-associated protein degradation machinery (or ERAD for short). To extract a faulty protein from the ER, proteins of the ER and outside the ER cooperate. First, an ERAD protein called Doa10 attaches a small protein tag called ubiquitin to the faulty proteins to mark them for destruction. Then, outside of the ER, a protein called Cdc48 ‘grabs’ the ubiquitin tag and pulls. But that is only part of the story. Many of the proteins made by the ER have tethers that anchor them firmly to the membrane, making them much harder to remove. To get a better idea of how the extraction works, Schmidt et al. rebuilt the ERAD machinery in a test tube. This involved purifying proteins from yeast and inserting them into artificial membranes, allowing closer study of each part of the process. This revealed that attaching ubiquitin tags to faulty proteins is only one part of Doa10's role; it also participates in the extraction itself. Part of Doa10 resides within the membrane, and this ‘membrane-spanning domain’ can interact with faulty proteins, loosening their membrane anchors. At the same time, Cdc48 pulls from the outside. This pulling force causes the faulty proteins to unfold, allowing them to pass through the membrane. Given these findings, the next step is to find out exactly how Doa10 works by looking at its three-dimensional structure. This could have implications not only for the study of ERAD, but of similar quality control processes in other organelles too. A build-up of faulty proteins can cause diseases like neurodegeneration, so understanding how cells remove faulty proteins could help future medical research.
journal_name
Elifejournal_title
eLifeauthors
Schmidt CC,Vasic V,Stein Adoi
10.7554/eLife.56945subject
Has Abstractpub_date
2020-06-26 00:00:00issn
2050-084Xpii
56945journal_volume
9pub_type
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