Structure of large proteasome unravelled

Publication in Proceedings of the National Academy of Sciences

Using advanced techniques, researchers have successfully unravelled the structure of a large human proteasome down to the atomic level. A proteasome is a protein complex that can break down other proteins that are redundant or damaged. The knowledge of the structure of this protein complex provides new insights into its degradation mechanism, say researchers in a publication in Proceedings of the National Academy of Sciences (PNAS). Biochemist Friedrich Förster, who began work at Utrecht University this year, contributed to this research in collaboration with the German Max-Planck Institute for Biochemistry.

Cryo-electron microscopy

The 26S proteasome is made up of no less than 32 different sub-units. Together with Professor Wolfgang Baumeister, Dr. Friedrich Föster was able to produce a detailed three dimensional image of the proteasome. They did this with the help of cryo-electron microscopy. The 26S proteasomes were isolated from cells and then frozen in thin layers of water. This allowed multiple copies of the protein complex to be viewed from different angles using electon microscopy. A computer was then used to combine the individual images of the proteasome in various orientations into a three dimensional image. This image provides insight into the way in which the distinct parts of the proteasome bind and work together.

The proteasome’s batteries

The researchers saw that energy carrying molecules, such as adenosine phosphates, were bonded to the proteasome. These molecules work like batteries: the ‘charged’ form is adenosine triphosphate (ATP), which becomes adenosine diphosphate (ADP) when energy is released. The proteasome needs this energy to unfold proteins. Proteasome 26S consists of six energy compartments, and Förster and his colleagues at the Max-Planck Institute discovered that these are all filled with energy carrying molecules when in resting state (i.e. when no proteins are being degraded). The energy from at least one of these ATP molecules is used, while the rest of the compartments still contain ‘charged’ ATP molecules.

In the long term, this clarification of the structure can form the basis for the development of medicines against cancer and diseases of the brain.

Sketch of the 26S proteasome, by Jüregen Plitzko (Max-Planck Institute of Biochemistry)