The life cycle of proteins

EU-LIFE Science Newsletter 3/2017

News from the Max Delbrück Center for Molecular Medicine (MDC), Germany

Some proteins behave in an unusual way: the older they become, the more stable they are. A research team has traced the life cycle of thousands of proteins from synthesis to disposal. 

Proteins have a plethora of different tasks and are being disposed in an orderly manner at the end of their lives. Scientists had thought that young and old proteins carry the same probability of being degraded. While this is true for most proteins, around one-tenth of the analyzed proteins don’t behave that way. Once these special proteins manage to reach a particular age, they remain unusually stable and live longer than expected.

This is the surprising finding of an international research team headed by Matthias Selbach of the MDC and Charité which was published in the journal Cell. The researchers traced the life cycle of thousands of proteins from synthesis to disposal.

They tracked the proteins’ lifecycles in cultures of human and mouse cells with mass spectrometry, allowing them to watch the creation and disposal of specific molecules over time. The measurements revealed that the cell initially produces an excessive number of certain types of proteins, the majority of which are immediately degraded. Those that remained then become stable.

This would explain why additional copies of a gene do not automatically result in more copies of a protein, as one would normally expect. In cases of trisomy, for example, an organism has three copies of a chromosome rather than two, normally leading to an overproduction of the proteins encoded by the genes on that chromosome. This often creates imbalances and leads to internal disequilibrium and stress for the cell.

For the proteins with the newly discovered properties, however, the cell can maintain equilibrium by simply dismantling copies of the protein early on, when too many are present. The scientists are now better able to explain the relationship between the ‘dose’ or rate of a gene’s productivity and the resulting quantity of the protein it encodes.

Most cases of trisomies result in the death of an organism prior to birth. But in the case of trisomy 21 (the cause of Down syndrome), the consequences are less serious. The reason why trisomies of different chromosomes result in such a diversity of effects is unclear, but this may be due to the lifecycles of some proteins encoded on the affected chromosome. Selbach is therefore keen to follow up the study with further research and is now looking at other cells with an abnormal genetic makeup.

Original Article: McShane E., Sin C., Zauber H., Wells J.N., Donnelly N., Wang X., Hou J., Chen W., Storchova Z., Marsh J.A., Valleriani A., Selbach M. (2016) Kinetic analysis of protein stability reveals age-dependent degradation. Cell. 167(3): 803–815

The image shows a ribosome, which is a complex of RNA (yellow) and numerous proteins. The proteins with the unusual characteristics are colored in blue; the “normal”, exponentially degraded protein is colored in red. Grey proteins could not be categorized. Image: Henrik Zauber, MDC