Like any appliance, proteins in living cells eventually become obsolete. The body relies on intricate machinery to tag proteins for recycling at a molecular factory, where they are chopped into pieces. Without recycling, the cell would overflow with molecular garbage and have scarce material to build new proteins.
In a paper posted online Wednesday, Aug. 12, by the journal Structure, researchers Maria Gaczynska, Ph.D., and Pawel Osmulski, Ph.D., of The University of Texas Health Science Center at San Antonio, and Mark Hochstrasser, Ph.D., of Yale University, describe how different parts of the factory communicate with each other to efficiently recycle cellular proteins.
The new findings hold potential ramifications for development of anti-cancer and anti-inflammation drugs, the researchers said.
Giant protein assembly
The machinery, called the UPS (ubiquitin-proteasome system), consists of several hundred proteins that direct obsolete proteins to the factory for recycling. The factory, a giant protein assembly called the proteasome, is equipped with gates, a warehouse and machines – catalytic centers that process the material.
“The gates are there to prevent wrong material – for example, proteins that should not yet be degraded – from entering the factory,” Dr. Gaczynska said. “The gates also help the factory to avoid a flood of raw materials that would choke and disrupt the factory operation. How to open the gates to allow the exact amount of the correct material inside the factory? This is where our work started.”
Gates observed in yeast
The scientists studied yeast proteasomes with an atomic-force microscope at the Health Science Center’s UT Institute of Biotechnology in the Texas Research Park. They discovered that the gates open briefly from time to time to admit materials for digestion. The opening is strictly correlated with the status of the machines, which are catalytic centers.
“It is sort of an invitation: My active centers are free; therefore, I can accept an order to perform a digest,” Dr. Osmulski said. “By signaling the gates how long to stay open, the factory works efficiently without waiting for supplies and without waste products littering the grounds.”
New way to regulate
The team also identified a small piece of machinery that is responsible for signaling the gates.
“We found that we can confuse the factory to keep the gate open by modifying that one piece of the active center,” Dr. Gaczynska said. “You can see immediately the opportunity to regulate the proteasome factory and the whole UPS activity in a totally new and unexplored way. If you also take into account that the gate talks back to the activity centers, the possibilities to control the whole factory are endless.”
Compounds that dampen proteasome activity have already been shown to suppress several cancers.
About the UT Health Science Center at San Antonio:
The University of Texas Health Science Center at San Antonio is the leading research institution in South Texas and one of the major health sciences universities in the world. With an operating budget of $668 million, the Health Science Center is the chief catalyst for the $16.3 billion biosciences and health care sector in San Antonio’s economy. The Health Science Center has had an estimated $36 billion impact on the region since inception and has expanded to six campuses in San Antonio, Laredo, Harlingen and Edinburg. More than 26,400 graduates (physicians, dentists, nurses, scientists and other health professionals) serve in their fields, including many in Texas. Health Science Center faculty are international leaders in cancer, cardiovascular disease, diabetes, aging, stroke prevention, kidney disease, orthopaedics, research imaging, transplant surgery, psychiatry and clinical neurosciences, pain management, genetics, nursing, dentistry and many other fields. For more information, visit www.uthscsa.edu.
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