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Structure of protein family that has been implicated in disease development identified

DALLAS – UT Southwestern Medical Center researchers – along with colleagues at the University of Pennsylvania – have determined the first atomic structure of a protein from the two-pore channel (TPC) family.

The study findings, published in Nature, could open the door to new therapeutic strategies since TPC activity has been shown to play roles in development of some diseases and in viral infection, said senior author Dr. Youxing Jiang, Professor of Physiology, Howard Hughes Medical Institute Investigator, and a W.W. Caruth, Jr. Scholar in Biomedical Research at UT Southwestern.

Dr. Jiangtao Guo, Weizhong Zeng, Dr. Youxing Jiang
Dr. Jiangtao Guo, Weizhong Zeng, Dr. Youxing Jiang

“This structure gives us a first glance of what this family of proteins looks like, which sets the foundation for future studies on how their ion channels function,” said Dr. Jiang. “These channels play an important role in health and disease since they mediate processing ranging from nutrient uptake by cells to the recycling of important molecules within a cell, like proteins and nucleic acids.”

More specifically, the findings could someday lead to targeted therapies for infections such as Ebola, whose course appears to be influenced by the functionality of the TPC channels, and other diseases, including Parkinson’s.

Many ion channels are critically important to a variety of functions in plants, animals, and humans – from how we sense the world around us to the pumping of the heart to the secretion of hormones – and TPC proteins are ubiquitously expressed in animals and plants as positively charged ion channels.

“Many biological processes rely on the rapid, coordinated transmission of information from one cell to another,” Dr. Jiang explained. “This transfer is accomplished by the generation of an electrical impulse by excitable cells, which happens when charged ions such as sodium, potassium, or calcium are able to cross a cell’s hydrophobic plasma membrane.”

To regulate those electrical impulses, cells use proteins called ion channels, which open and close in response to specific signals that allow ions to cross the plasma membrane and change the cell’s membrane potential.

Using AtTPC1 – the TPC1 channel from the plant Arabidopsis thaliana – as the model system, the investigators worked out the first three-dimensional X-ray crystal structure of the 12-membrane-spanning TPC family, as well as determined a comprehensive functional characterization of the channel.

The study is also groundbreaking because of another major finding.

“We’ve shown for the first time the voltage-gated channel structure in its resting state, which provides crucial insights into the general voltage-gating mechanism of all cells,” said Dr. Jiang. “By correlating structure to function, the results of our research provide fundamental knowledge about how voltage-regulated cation channels work.”

Dr. Jiang explained that this long-awaited structural view of a channel voltage sensor in the resting state enables scientists to reconstruct the opening and closing of a voltage-gated ion channel.

“Our current work challenges conventional wisdom in the field on the opening and closing mechanisms used by these proteins in response to membrane potential changes, a subject that has been under heated debate over the last decade,” he said.

Other UT Southwestern authors from the Department of Physiology who contributed to this study include lead author Dr. Jiangtao Guo, postdoctoral researcher; Weizhong Zeng, research specialist; Dr. Qingfeng Chen, postdoctoral researcher; Changkeun Lee, research scientist; Liping Chen, with the Howard Hughes Medical Institute; and Yi Yang, research technician.

The study was supported by the Howard Hughes Medical Institute, the National Institutes of Health, and the Welch Foundation.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty includes many distinguished members, including six who have been awarded Nobel Prizes since 1985. The faculty of more than 2,700 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in 40 specialties to about 92,000 hospitalized patients and oversee approximately 2.1 million outpatient visits a year.


Media Contact: Debbie Bolles

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