The theory behind this phenomenon, also known as the protein burden, is that accumulation of excessive protein within the cell will deplete the cell of resources, such as energy. The limit required to reach this burden though, is not the same for all proteins. Green fluorescent protein (GFP) is a harmless protein artificially introduced into cells for visualizing the insides of the cell. When GFP levels were increased within yeast cells, they found that GFP up to 15% of total protein content was harmless to the cells. Using this measure as a standard, Associate Professor Hisao Moriya’s team set out to estimate the burden limit of functional proteins in the cells. 29 proteins essential for energy production were subsequently over-produced.
While many of these proteins also had limits close to 15%, suggestive of their harmless nature, some of the proteins showed growth retardation and other unpleasant effects at lower levels. One such protein was found to accumulate within the mitochondria. Clogging the mitochondria prevents cells from producing oxygen. Another protein was found to undergo structural changes and aggregate into big pieces. Another reason for some of these proteins having a low burden limit, was due to metabolic disturbances induced when they were produced even slightly higher than usual. When these proteins were inactivated by mutations, their burden limit increased. Lastly, the researchers also found that certain proteins showed growth retardation, even at very low levels. Further investigation revealed that such proteins are programmed to remain at inherently low levels. Therefore, even small changes to their concentrations can be dangerous.
This study paved a framework for biologists to make distinctions between proteins based on how toxic they are when present in abnormal amounts. These differences could be attributed to the function, structure or genetic programming for that protein. Scientists can hope to use this framework to investigate proteins that are associated with diseases such as Alzheimer’s disease or Parkinson’s disease.
The protein burden: Each protein has a distinct function within cells. Proteins are found in millions within the cell, and are synthesized or increased when required. Their levels subside when the cell doesn’t require them anymore. In certain conditions, such as neurodegenerative disorders, the levels of some proteins inherently remain high. Because the cell is not used to this, a battle to reduce these proteins ensues. This not only uses up the cell’s energy but damages the cell in the process.
Yuichi Eguchi, Koji Makanae, Tomohisa Hasunuma, Yuko Ishibashi, Keiji Kito, Hisao Moriya. Estimating the protein burden limit of yeast cells by measuring the expression limits of glycolytic proteins. eLIFE, 2018;7:e34595.
Reference (Okayama Univ. e-Bulletin & OU-MRU): Associate Professor Moriya’s team
e-Bulletin Vol.3 (2013)：Measuring the copy number limits of all genes in budding yeast. – First time ever for any organisms –.
OU-MRU Vol.36 (2017)：Overloading of protein localization triggers cellular defects.
OU-MRU Vol.37 (2017)：Protein dosage compensation mechanism unravelled.
Associate Professor Hisao Moriya, Ph.D.
Research Core for Interdisciplinary Sciences, Okayama University,
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Okayama University Medical Research Updates （OU-MRU）
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About Okayama University
Okayama University is one of the largest comprehensive universities in Japan with roots going back to the Medical Training Place sponsored by the Lord of Okayama and established in 1870. Now with 1,300 faculty and 13,000 students, the University offers courses in specialties ranging from medicine and pharmacy to humanities and physical sciences. Okayama University is located in the heart of Japan approximately 3 hours west of Tokyo by Shinkansen.
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