The life cycle of proteins

Some proteins behave in an unusual way: the older they become, the more stable they are. A research team at the Max Delbrück Center in the Helmholtz Association (MDC) has now published this surprising finding in the journal Cell. Their work has traced the life cycle of thousands of proteins from synthesis to disposal. The results are relevant for diseases where there are surplus copies of certain genes.

What’s the life of a protein like? First, a blueprint is transcribed from a gene and eventually becomes translated into a chain of protein building blocks. This chain folds itself into a three-dimensional molecule that then takes on functions such as helping create a cellular structure, forming a molecular machine or transporting other molecules. The life of a protein ends when it is broken down into its components by a molecular shredder.

Until now, surprisingly little has been known about protein mortality overall. Scientists had thought that young and old proteins have the same risk of being degraded. According to this rule, proteins degrade just the way radioactive substances randomly decay over time: A radioactive atom has always a 50% probability to decay during a given half life period, irrespective of the actual age of the atom.  That’s why the “half-life” of a protein is an firmly established term in lab jargon.

A tenth of all protein species do not follow the rule

Actually, some proteins behave completely differently. Around one-tenth of protein species analyzed become more stable with increasing age. This is the surprising finding of an international research team headed by Prof. Matthias Selbach of the MDC and Charité – Universitätsmedizin Berlin in the prestigious journal Cell. Working with partners from the Max Planck Institute of Colloids and Interfaces and other labs, the researchers traced the life cycle of thousands of proteins from synthesis to disposal. This makes them the first to track the course of protein degradation processes in the cell over time.

Tracking the life of proteins

To track protein lifecycles, the researchers fed cultures of human and mouse cells with an artificial protein building block AHA for a short time. The cells incorporated this subunit into the new proteins they made. The researchers could then use a trick which allowed them to pull out the AHA containing proteins from the complex mixture of proteins. By doing this at different time points after they fed the cells they could measure how much protein was remaining. The method they used, mass spectrometry, allowed the scientists to detect and measure the amount of proteins. Mass spectrometers work like very fine weighing scales; they can catalog the mass of countless individual molecules. This allowed the scientists to watch the disposal of specific molecules over a period of 32 hours.

Most of the proteins are disposed of – the rest remain stable

The ribosome 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. Rendering: Henrik Zauber, MDC.

The measurements revealed that the cell initially produces an excessive number of certain types of proteins. The majority of the newly produced proteins are immediately degraded, and the rest remains stable. Proteins with these characteristics are particularly common in protein complexes: machines built of several different proteins. In these complexes the proteins may be safe from degradation. Group leader Prof. Matthias Selbach says: “This reminds me of hatching turtles at the beach. Many of the animals get eaten by preying birds while they try to reach the ocean. Once the turtles get to the water, they are safe.“

The researchers can only speculate what purpose the phenomenon may serve. “The proteins that are produced in excess could provide a constant ready-made foundation for the complex,” says PhD student Erik McShane, lead author of the paper. “This means that the cell wouldn’t have to coordinate the production of several proteins needed for the machine; it would only have to control the production of one important subunit that would then limit the functions of the machine. Then the superfluous components made ahead of time are simply degraded.”

The consequences of a gene overdose

The results are also relevant for diseases where there are additional copies of particular gene. 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. “We 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,” explains Matthias Selbach.

Most cases of trisomies result in the death of an organism prior to birth. But in the case in which humans contain three copies of chromosome 21 (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 different lifecycles of some proteins encoded on the affected chromosome.

Selbach is therefore keen to follow up the study with further research. “We are now looking at other cells with an abnormal genetic makeup, in order to improve our understanding of the consequences of multiplied gene segments,” he says.

Erik McShane1, Celine Sin2, Henrik Zauber1, Jonathan N. Wells3, Neysan Donnelly4, Xi Wang1, Jingyi Hou1, Wei Chen1, Zuzana Storchova4,5, Joseph A. Marsh3, Angelo Valleriani2 and Matthias Selbach1,6 (2016): „Kinetic analysis of protein stability reveals age-dependent degradation.“ Cell. doi:10.1016/j.cell.2016.09.015

1Max Delbrück Center for Molecular Medicine, Berlin, Germany; 2Max Planck Institute for Colloids and Interfaces, Potsdam, Germany; 3MRC Human Genetics Unit, University of Edinburgh, Edinburgh, United Kingdom; 4Max Planck Institute for Biochemistry, Martinsried, Germany; 5TU Kaiserslautern, Kaiserslautern, Germany; 6Charité – Universitätsmedizin Berlin, Berlin, Germany

Featured Image: Fluorescing Chromosomes in the microscope. The trisomic chromosomes 11 and 5 are colored pink and green, respectively. All the other chromosomes appear blue. Image: Neysan Donnelly, MPI of Biochemistry.

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