Lysine Acetylation Targets Protein Complexes and Co-Regulates Major Cellular Functions
Chunaram Choudhary, Chanchal Kumar, Florian Gnad, Michael L. Nielsen, Michael Rehman, Tobias Walther, Jesper V. Olsen, Matthias Mann
Science, July 2009
Manuscript Number: 1175371
Abstract: http://www.sciencemag.org/cgi/content/abstract/1175371
Researchers identify important molecular disease-switches in humans
Proteins, the molecules of life, are not only the building blocks of living organisms; they also serve as work crews that perform most essential functions of life. A specific protein can perform more than one task, and how it acts in our body can be regulated by adding small molecules to it, which then act as "switches" for various tasks.
It is already known that a certain protein-modification called acetylation plays an important role in regulating the normal workings of a cell - and if faulty or not properly controlled this modification can play a significant role role in ageing and human diseases such as cancer, Parkinson and Alzheimer.
Drugs that can fix this faulty protein-regulation show great promise in treating human cancers. Also, recent research shows that our somatic cells (such as cells from hair, blood, skin etc.) can be converted back to function as stem cell-like cells which provide hope for treating many human diseases. Use of these drugs can significantly improve the success rate of generating such stem cells.
So to understand the complex language of life the researchers need to find out how every protein in our body work, and to identify all the switches - such as the acetylation switches - for all of the proteins. But until now technological limitations have prevented the researchers from fully identifying and cataloguing all the possible acetylation protein-modications on all human proteins.
However, using cutting-edge technology a team headed by professor Matthias Mann at the Novo Nordisk Foundation Center for Protein Research at the University of Copenhagen and the Max-Planck Institute for Biochemistry in Germany, has now managed to catalogue 3600 switches (acetylation sites) present on 1750 proteins.
The study has expanded the currently known number of acetylation-switches by more than six fold which provides the first global view of this protein-modification.
The researchers have discovered that the acetylation-modification mainly occurs on proteins that function together and that these switches have far wider implications than previously known. If the researchers, for instance, add an acetylation-switch to a protein (Cdc28) in yeast, which is important for its growth, it can impair the function of the protein and thus the survival of the yeast-organism.
The researchers believe that they may now be able for the first time, to quantify acetylation changes in response to specific perturbations such as treatment of cancer cells with drugs that act to fix faulty acetylation-switches involved in diseases.