The National Institutes of Health is the first to develop a 3D structure of flicker

3D structure of a fluorescent protein

Image: This rotating image shows the 3D structure created by the NIEHS researchers from the scintillating protein. The researchers used Cryo-EM and other techniques to show how pathological mutations on the protein can lead to mitochondrial diseases. The video is zoomed in to the protein interface where many of the disease mutations occur.
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Credit: Graphics and video courtesy of AA Riccio, NIEHS

Researchers from the National Institutes of Health have developed a 3-D structure that allows them to see how and where pathological mutations on a flash protein can lead to mitochondrial diseases. Protein is involved in helping cells use the energy our bodies convert from food. Before developing this 3D structure, researchers only had models and were unable to determine how these mutations contribute to the disease. Mitochondrial diseases are a group of genetic conditions that affect 1 in 5,000 people and have very few treatments.

“For the first time, we can map the mutations that cause a number of these devastating diseases,” said lead author Amanda A. Replication kit, part of the National Institutes of Health. “Clinicians can now see where these mutations lie and can use this information to help identify causes and help families make choices, including decisions about having more children.”

The new findings will be particularly relevant to the development of targeted therapies for patients with mitochondrial diseases such as progressive external ophthalmoplegia, a condition that can lead to a loss of muscle function associated with eye and eyelid movement; Perrault syndrome, a rare genetic disorder that can cause hearing loss; pediatric spinal cord ataxia, an inherited neurological disorder; and hepatobiliary DNA (mtDNA), a genetic disease that can lead to liver failure and neurological complications during childhood.

The paper that appears in Proceedings of the National Academy of Sciences It shows how NIEHS researchers were the first to accurately map clinically relevant variants in Twinkle Helix, the enzyme that removes the double helix of mitochondrial DNA. Blink structure and all coordinates are now available in open data Protein Data Bank This is freely available to all researchers.

“Twinkle’s structure has eluded researchers for many years. It’s a very difficult protein to work with, noted William C. Copeland, PhD, who leads the mitochondrial DNA cloning group and is the corresponding author on the paper. “By stabilizing the protein and using the best equipment in the world, we were able to build the last missing piece in order to make up for human mitochondrial DNA.”

The researchers used cryogenic electron microscopy (CryoEM), which allowed them to see inside the protein and the complex structures of hundreds of amino acids or residues and how they interact.

Mitochondria, which are responsible for energy production, are particularly susceptible to mutations. mtDNA mutations It can disrupt its ability to efficiently generate energy for the cell. Unlike other specialized structures in cells, mitochondria have their own DNA. In the cell nucleus there are two copies of each chromosome, but in the mitochondria there can be thousands of copies of mtDNA. The presence of a large number of mitochondrial chromosomes allows the cell to tolerate some mutations, but the accumulation of many mutated copies leads to mitochondrial disease.

To conduct the study, the researchers used a clinical mutation, W315L, known to cause progressive external ophthalmoplegia, to resolve the structure. Using CryoEM, they were able to observe thousands of protein molecules appearing in different directions. The final structure shows a circular, multi-protein arrangement. They also used mass spectrometry to check the structure and then ran computer simulations to understand why the mutation caused disease.

Within a twinkle, they were able to identify as many as 25 disease-causing mutations. They found that many of these pathological mutations bind directly at the junction of two protein subunits, suggesting that mutations in this region would impair how the subunits interact and render helicase unable to function.

“Arranging a shimmer is a lot like a puzzle. A clinical mutation can change the shape of the shimmering pieces, and they may no longer fit together properly to do the intended function,” Ricciu explained.

Matthew J. said: “It is unusual to see a single paper explaining so many clinical mutations. Thanks to this work, we are one step closer to obtaining information that can be used to develop treatments for these debilitating diseases.”

Grant: This research was supported by the NIEHS Internal Research Program. Z01ES065078, Z01 ES065080, Z01 ES043010, ZIC ES 103326, NIH P41-GM103311.

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Reference: Riccio AA, Bouvette J, Perera L, Longley MJ, Krahn JM, Williams JG, Dutcher R, Borgnia MJ, Copeland WC. Structural Insight and Characterization of Human Twinkle Helicase in Mitochondrial Disease. PNAS;

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