Kenneth Dill, right, and co-authors Adam de Graff, left, and Michael Hazoglou, center, standing beside a computerized display of three identified proteins at risk for oxidation: (Left) – A normal protein that has a balance of charges not at risk for oxidation; (Center) – The RBAp48 protein is at risk because of a high negative charge (red area), which are histones known in memory loss. (Right) – Telomerase protein is at risk for oxidation because of high net positive charge (blue area). Credit: John Griffin, Stony Brook University
When people turn about 80 yo, ~half of the body’s proteins are damaged by oxidation. Oxidation occurs because of random chemical degradations that are associated with converting food to energy in the presence of oxygen. Oxidation in the human body, mediated by free radicals, damages cellular proteins, lipids, DNA, and other cellular structures that contribute to disease processes.
The Stony Brook research team used physics principles and computer analysis to evaluate protein electrostatics, or charges. They found that short, highly charged proteins are particularly susceptible to large destabilization and that even a single oxidation event within these proteins is sufficient to unfold its normally balled-up, folded structure.
“Our paper explains the molecular mechanism by which natural chemical processes of aging affect our proteins,” says Dr. Dill. “Our method predicts which proteins are the most at risk of unfolding when they get damaged. We then applied the principle in searching protein databases. Interestingly, we found that the proteins most at-risk for oxidative unfolding included 20 proteins that span a wide-spectrum of functionalities, all of which had been known by researchers previously to be associated with aging.”
Highlights •Proteins undergo random damage from oxidation in aging •Oxidative damage can change side chain charge, leading to protein stability loss •Highly charged proteins are at particular risk of large oxidative stability loss •Key pathways and aggregates of old cells are enriched in highly charged proteins
The list of proteins includes transcription factors, histone and histone-modifying proteins, ribosomal and telomeric proteins, and proteins essential for homeostasis. Telomerase proteins play a major role in aging of cells and cancer development by the extending of telomeres; and histones, which are DNA-binding proteins are known to be relevant for many processes, including memory loss and cancer. The team will continue to use the method to search further databases of proteins to seek additional proteins that may be important to aging and age-related diseases.
Dr. Dill explained that the mechanism provides a foundation to for scientists to better understand how oxidation causes damage to proteins in aging cells. The team will continue to use the method to search further databases of proteins to seek additional proteins that may be important to aging and age-related diseases.
The research, he added, could be a first step toward finding other proteins, not currently suspected, that are susceptible to high oxidation, instability and age-related diseases. The proteins could prove to be the key to targeted treatments against certain age-related diseases. http://www.newswise.com/articles/study-reveals-proteins-most-associated-with-aging
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