Scientists are now able to "see" a structure that acts as an atomic-size sorter for cells. Without it, many important life functions—nerve signal firing, heartbeat, hormone secretion—could not occur.
The "selectivity filter," never before visualized in such exquisite detail, provides precise biochemical conditions needed for ions during their intercellular travel.
Ions, the electrically charged atoms that power many vital functions, traverse cell membranes through specialized proteins called ion channels. The proteins provide pathways between the inner part of the cell and the exterior. The selectivity filter is the essential part of the pathway.
The three-dimensional image of the selectivity filter, revealed by X-ray crystallography, is the culmination of several years’ work by Rockefeller University researchers from the Laboratory of Molecular Neurobiology and Biophysics. Professor and Howard Hughes Medical Institute Investigator Roderick MacKinnon, M.D., who heads the lab, and his colleagues describe their work in the Nov. 1 issue of Nature.
The image shows the selectivity filter of the channel that only the potassium ion can use to cross the cell membrane. In the same issue of Nature, MacKinnon and his colleagues report in another paper how the filter changes its shape under different environmental conditions within the body.
"We know the overall channel structure will be similar in channels that conduct potassium, sodium and calcium ions, but the chemistry in the selectivity filter will be unique in each specific case," says MacKinnon.
The selectivity filter also occupies a unique place in the potassium ion channel. The overall protein consists of four subunits, like four staves of a barrel. Inside the protein is a narrower tube called the selectivity filter where the potassium ion is recognized by the protein. The selectivity filter works as a sorter that chemically senses the ions as they go through the channel. When it senses an ion that should not be inside the channel, the filter forbids it to enter.
The chemical principles of binding revealed in the selectivity filter bring the basic science of ion channels to a new plateau. The discovery will help biomedical researchers understand genetic and biochemical abnormalities that effect the body’s ion channel proteins.
Yufeng Zhou, Ph.D., a postdoctoral researcher in MacKinnon’s laboratory and first author on the selectivity filter structure paper, is interested specifically in what makes the potassium ion channel susceptible to conduction abnormalities.
One well-known conduction abnormality is "long QT syndrome," which can result in sudden cardiac arrest. Long QT syndrome, also known as "torsades de pointes," is a prolongation of the Q to T interval, shown on an electrocardiogram. The abnormality is caused by changes in the conduction rate of the potassium ion channels. Long QT syndrome can occur either as a result of a genetic condition or as a side effect of many drugs.
"There are many heart medications, anti-virals, anti-seizure and anti-malarial drugs that cause long QT in some people. There are as many as 100 known drugs that cause long QT," says Zhou.
The U.S. Food and Drug Administration (FDA) has documented about 40 commercially available drugs that cause long QT in a small number of people. Even the highly sought antibiotic, Cipro, has demonstrated some long QT effects.
"It’s hard to tolerate even one in a thousand instances of a drug-induced, potentially fatal conduction abnormality," says MacKinnon. "But it’s hard also to test for because there’s some unknown mix of susceptibility factors we’re still trying to understand. If we can discover the abnormality at an early stage, through understanding the binding conditions, it may be lifesaving," he added.
The potassium ion channel, a protein described at the atomic level by MacKinnon and his colleagues for the first time in 1998, has yielded even more of its structural character to science this year.
In June, MacKinnon and his colleagues solved a puzzle involving another area of the ion channel, the inactivation gate. That work resulted also in a Nature paper on June 7. Using techniques to produce precise mutations in the channels, coupled with X-ray crystallography, the researchers deduced that one of four long "tails," called inactivation gates, at the end of the channel can slide into the channel’s pore and shut it down.
This helps to explain how the channels slam shut, regulating the frequency of nerve signal firing and other critical bodily functions. The research greatly refines our understanding of how potassium ion channels manage to close milliseconds after opening, and like the newly seen selectivity filter, offers insights that will aid in designing drugs that control the channels more precisely.
Learning the chemical principles of all trans-membrane channel selectivity filters, coupled with the other mechanistic features of the proteins, will help biomedical researchers understand a range of channel abnormalities. Cystic fibrosis, for example, one of the most common heritable diseases in Caucasian populations, is caused by an abnormality of a chloride ion channel.
Authors include Zhou, MacKinnon, Research Assistant Amelia Kaufman and Joao H. Morais-Cabral, Ph.D. Cabral, who is now at Yale University is the first author on one of the two Nov. 1 Nature papers.
The work reported in the Nov. 1 Nature papers was funded by a grant from the NIH and the Howard Hughes Medical Institute.
John D. Rockefeller founded Rockefeller University in 1901 as The Rockefeller Institute for Medical Research. Rockefeller scientists have made significant achievements, including the discovery that DNA is the carrier of genetic information. The University has ties to 21 Nobel laureates, six of whom are on campus. Rockefeller University scientists have received the award in two consecutive years: neurobiologist Paul Greengard, Ph.D., in 2000 and cell biologist Günter Blobel, M.D., Ph.D., in 1999, both in physiology or medicine. At present, 32 faculty are elected members of the U.S. National Academy of Sciences, including the president, Arnold J. Levine, Ph.D. Celebrating its centennial anniversary in 2001, Rockefeller — the nation’s first biomedical research center—continues to lead the field in both scientific inquiry and the development of tomorrow’s scientists.
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