Discoveries concerning the controlled process of cell protein degradation have earned three scientists the Nobel Prize in Chemistry for 2004.
Aaron Ciechanover and Avram Hershko from the Technion, Israel Institute of Technology, Haifa, and Irwin Rose from the University of California, Irvine, share the $1.3 million prize for discovering the process by which a protein called ubiquitin attaches itself to unwanted proteins, giving them the 鈥渒iss of death鈥� that marks them for destruction.
鈥淚t鈥檚 a way of tagging proteins that need to be degraded, either because they reach the end of their useful life, or they are damaged, or there are too many of them,鈥� says Richard Sullivan from Cancer Research UK.
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While work on understanding how proteins are made has received lots of attention, work on understanding how proteins are degraded has been less publicised. But it is now known that when the process goes wrong it can result in cancer, cystic fibrosis and brain degenerative conditions such as Parkinson鈥檚 and Alzheimer鈥檚 disease.
鈥淎 number of processes are being discovered that rely on ubiquitination,鈥� says Brian Austen of St. George鈥檚 Hospital Medical School, London, UK. These processes include DNA repair and transcription, protein quality control and the immune response.
Enzyme soup
In 1980, the three scientists discovered that a protein, later found to be ubiquitin, forms a stable covalent bond to unwanted proteins. 鈥淗ershko used a really simple system in order to make the discovery 鈥� just a soup of enzymes and proteins,鈥� says John Mayer, a professor of molecular cell biology from the University of Nottingham Medical School, UK. 鈥淔rom this he was able to show the target protein must be ubiquitinated.鈥�
Later work proved that more than one ubiquitin molecule attaches to the same protein and together they act as an escort, delivering the targeted protein to a barrel-shaped structure called a proteasome, and leaving it to be engulfed. The proteasome breaks up the protein and spits out the disassembled protein parts.
They went on to further their understanding by identifying three types of enzyme involved in the process. The third type 鈥� the ubiquitin protein ligases 鈥� plays the important role of identifying the target protein.
Cinderella story
The process occurs in cells all over the body, making the name ubiquitin, from the Latin ubique 鈥� meaning everywhere 鈥� particularly suitable.
But their work was not instantly recognised as important. 鈥淚t鈥檚 a Cinderella rise from rags to riches,鈥� says Mayer. 鈥淎t first nobody cared about their work and those that knew something about it didn鈥檛 believe it.鈥�
Understanding the ubiquitination process allows drugs to be developed that can accurately target it. One such cancer drug is currently in its final stage of development and undergoing human clinical trials. By inhibiting ubiquitination in the cancerous region, proteins build-up and poison the cancerous cells. Other drugs for various diseases could follow. 鈥淭here will be a new understanding and a new treatment of disease,鈥� says Mayer. 鈥淣o doubt about it.鈥�
So as time goes on the protein degradation process 鈥� first understood by Aaron Ciechanover, Avram Hershko and Irwin Rose 鈥� could become even more important. 鈥淭he ubiquitin system definitely deserves the Nobel Prize,鈥� says Mayer.