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NIH study of aquaporins could hold clues to genetic errors in eye structure, damage to eyes from diabetes and smoking, as well as the advance of cataracts in aging eyes.
Researchers have achieved dynamic, atomic-scale views of a protein needed to maintain the transparency of the lens in the human eye. The work, funded in part by the National Institutes of Health, could lead to new insights and drugs for treating cataract and a variety of other health conditions.
Abnormal development or age-related changes in the lens can lead to cataract—a clouding of the lens that causes vision loss. Besides age, other risk factors for cataract include smoking, diabetes, and genetic factors. Mutations in the AQP0 gene can cause congenital cataract and may increase the risk of age-related cataract.
"The AQP0 channel is believed to play a vital role in maintaining the transparency of the lens and in regulating water volume in the lens fibers, so understanding the molecular details of how water flows through the channel could lead to a better understanding of cataract," said Dr. Houmam Araj, who oversees programs on lens, cataract and oculomotor systems at NIH’s National Eye Institute (NEI), which helped fund the research.
The research was a collaboration between investigators at the University of California, Irvine and the Janelia Farm Research Campus in Ashburn, Va., a part of the Howard Hughes Medical Institute (HHMI). Drs. James Hall and Douglas Tobias led the effort at UC Irvine. Dr. Tamir Gonen led the effort at Janelia Farm.
In prior studies, Dr. Gonen had examined the atomic structure of the AQP0 protein by X-ray crystallography, which involves crystallizing a protein and bombarding it with X-rays. But X-ray crystallography does not work well for large groups of proteins or for proteins in motion. So in the new study, the researchers first used electron microscopy to view AQP0 and calmodulin bound together. Then they combined their microscopy and crystallography data to generate computerized models of how the two proteins interact and to identify the most critical amino acids (the building blocks for proteins) within AQP0. To test their models, they neutralized those amino acids one-by-one in the actual AQP0 channel.
"Calmodulin essentially throws a molecular switch that moves in and out of the water pore, like the gate valve of a plumbing fixture," Dr. Hall said.
This new view of AQP0 could help lead to new approaches for treating cataract, Dr. Hall said. Cataracts are the most common cause of blindness worldwide. In the U.S., they affect about one in six people over age 40 and half over age 80. Congenital cataracts (present from birth) affect about 1 in 5000, American children.
Cataracts can be successfully treated with surgery, in which the cloudy lens is removed and replaced with an artificial plastic lens. But the new findings "may be a step toward learning how to prevent or delay cataracts," said Dr. Hall.
The study, by Reichow SL, Clemens DM, Freites JA, Németh-Cahalan KL, Heyden M, Tobias DJ, Hall JE, and Gonen T., is titled: "Allosteric mechanism of water-channel gating by Ca2+–calmodulin." and available in Nature Structural and Molecular Biology, July 2013. DOI: 10.1038/nsmb.2630.
The new findings also provide inroads to understanding how calmodulin interacts with a variety of protein channels, and thus could open doors to new drugs for other common health conditions. In addition to aquaporins, our bodies rely on a vast menagerie of channels, many of which are regulated by calmodulin. For example, calmodulin helps control the gating of ion channels, which allow the passage of ions (charged particles) in and out of our cells and are essential for nerve cell firing, muscle contraction, and the rhythmic beating of the heart. This study provides the first structural model of calmodulin bound to any complete protein channel.
Drs. Daniel Clemens and Steve Reichow were co-first authors on the study. NIH support for the study came from NEI (grants EY005661, EY018768), the National Institute of General Medical Sciences (NIGMS grant GM079233), a joint program on "Making Sense of Voltage Sensors" co-funded by NIGMS and the National Institute of Neurological Disorders and Stroke (grant GM086685), and the National Library of Medicine (grant LM007443). Additional support came from HHMI, the National Science Foundation, and the German Academy of Sciences.
To set up an interview with Dr. Hall, please contact Tom Vasich at UC Irvine (firstname.lastname@example.org, 949-824-6455).
The National Eye Institute, part of the National Institutes of Health, leads the federal government's research on the visual system and eye diseases. NEI supports basic and clinical science programs that result in the development of sight-saving treatments. For more information, visit http://www.nei.nih.gov.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
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Original press release:http://www.nei.nih.gov/news/pressreleases/080213.asp