Just as old plastic bottles are ground up at the recycling plant to be used to make new ones, so cells also recycle proteins. Proteins which are damaged or no longer required are sent to one of several different recycling plants in the cell. Once there, they are chopped up into their constituent parts so they can be used to build entirely new proteins. In 2015, more structures of one of these recycling plants, the proteasome, were made public by the wwPDB than any other molecule. More than 100 proteasome structures were added to the archive.
The proteasome, itself made up of proteins, is composed of a ‘core� and two ‘caps�. The core, show in spacefill on the left, is a cylindrical complex built of two copies each of 14 different protein subunits arranged in four stacked rings. At each end of the core is a ‘cap� complex, which is a collection of further different proteins.
The cap proteins select which molecules are to be degraded and then feed them into the hollow centre of the core. Here, three active sites cleave the peptide bonds between the amino acids of the protein to be recycled. This selection process ensures the correct proteins are chopped up, and the proteasome doesn't destroy every protein it encounters. Recycling of proteins by the proteasome is critical for the function of the cell, not just because it provides a supply of recycled amino acids to make more proteins, but because removing key signalling molecules is a way of controlling cell homeostasis- once the message has been transmitted, the proteasome shoots the messenger!
The vast majority of the proteasome core structures added to the wwPDB archive in 2015 were from Michael Groll’s group at Center for Integrated Protein Science, which we processed here at PDBe.
In one JACS paper, Groll and Eva Huber describe over 40 structures which provide a detailed picture of the substrate specificities of proteasomes. This may well help develop subunit-specific inhibitors, which could act as chemotherapeutics. Inhibition of proteasomes by drugs such as bortezomib and carfilzomib is already being used as a treatment for some blood cancers, but resistance to these drugs is hampering their use.
In a second paper in the journal Structure, Groll’s group solved nearly 50 different proteasome structures to examine how different mutations result in resistance to these anti-cancer drugs. The image below shows Bortezomib covalently bound to the proteasome in entry 4qvl.
