A research team led by structural biologists from Vanderbilt University has come up with the first detailed molecular explanation for a factor that may contribute to the so-called cystic fibrosis (CF) “gender gap.”
There is evidence that women with CF die on average two to three years earlier than do men with the devastating lung airway disease. The researchers said their findings, which were published in Science Advances, an offshoot of Science magazine, may lead to improved treatments for CF.
“We think we may be illuminating an important mechanism that contributes to women succumbing earlier to cystic fibrosis,” said Charles Sanders, Ph.D., professor of Biochemistry and Medicine and the Aileen M. Lange and Annie Mary Lyle Professor of Cardiovascular Research at Vanderbilt.
A collaborative team of structural biologists and channel biophysicists that included Sanders and Vanderbilt postdoctoral fellow Brett Kroncke, Ph.D., the paper’s first author, focused on a potassium ion channel called KCNQ1, which in the lung is regulated by a protein called KCNE3.
Cystic fibrosis is caused by mutations in a gene encoding the CF transmembrane conductance regulator (CFTR), an ion channel that normally maintains proper salt balance in the lung. Both males and females can inherit mutations in the CFTR gene, but the female hormone estrogen may make matters worse.
Normally CFTR function is supported by the potassium ion channel KCNQ1, when it is locked in its open position by its regulatory protein, KCNE3. But when estrogen stimulates attachment of a phosphate group to KCNE3, the protein can’t do its job.
“As a result, when the channel should be open, struggling to help restore an already disrupted salt balance, it doesn’t do that,” Sanders said. “This may make an already unfortunate situation worse in a gender-specific manner.”
The researchers used sophisticated techniques, including nuclear magnetic resonance (NMR) spectroscopy, electrophysiology, and computational modeling, to create the first three-dimensional model for how estrogen, by interfering with the KCNE3/KCNQ1 complex, disrupts channel function.
In the heart, mutations in the regulation of the same potassium ion channel are associated with long QT syndrome, which increases the risk of life-threatening cardiac arrhythmias.
“The model of the channel that we developed can now also be applied to long QT syndrome and other disorders that are associated with this channel,” Sanders said.
Sanders, one of the paper’s three corresponding (senior) authors, said the paper “illustrates the power of the integrative approach to structural biology, which has been whole-heartedly championed by Vanderbilt’s Center for Structural Biology.”
“It relies heavily on experimental work using NMR spectroscopy, biochemistry, electrophysiology and a very heavy dose of computational modeling,” he added. “Without all of these things coming together, this project would not have happened.”
The other corresponding authors were Wade Van Horn, Ph.D., of Arizona State University in Tempe, and Carlos Vanoye, Ph.D., of Northwestern University Feinberg School of Medicine in Chicago.
Other contributors included Jens Meiler, Ph.D., professor of Chemistry and associate professor of Pharmacology and Biomedical Informatics at Vanderbilt, and Alfred George, M.D., chair of Pharmacology at Northwestern and former director of the Division of Genetic Medicine at Vanderbilt.
The research was supported in part by National Institutes of Health RO1 grants DC007416, HL122010 and GM113355.
