You loosen, I pull
Two proteins work together to remove faulty proteins from a cell compartment.
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.
Originally published at https://elifesciences.org/digests/56945.
