UI researchers discover new activity in cystic fibrosis protein

Even well-studied proteins can reveal surprises. University of Iowa scientists have discovered a new enzyme activity for the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is the protein that is defective in cystic fibrosis, a common life-threatening genetic disease that affects primarily the lungs and pancreas of young people. The discovery, which appeared in the Dec. 26, 2003 issue of Cell, helps solve a long-standing puzzle about how this important protein works.

CFTR forms a channel, or pore, in the membrane of airway cells. When the channel is open, the salt chloride flows through it from one side of the membrane to the other. It has been known for many years that CFTR channel opening requires a molecule called ATP and that CFTR has an enzymatic activity called ATPase that uses ATP. ATP is the energy currency of the cell and the ATPase reaction spends the energy of ATP to power enzyme activity. Because chloride flows passively through the CFTR channel, it has long seemed puzzling that the opening of CFTR would require the substantial energy of ATP. Moreover, energy from ATP is not required to fuel any other ion channel.

The UI study now reveals that CFTR can function as an adenylate kinase enzyme. Like an ATPase, the adenylate kinase reaction uses ATP. But in contrast to an ATPase, an adenylate kinase enzyme also uses a related molecule called AMP. Importantly, the adenylate kinase neither consumes nor produces energy, but it controls channel opening. The study also suggests that in normal cells it is this enzyme activity rather than the ATPase that opens the CFTR channel.

“We think that in the normal physiologic context where AMP is present, CFTR would function as an adenylate kinase,” said Christoph Randak, M.D., UI postdoctoral scholar in the UI Department of Internal Medicine and lead author of the study. “Thus, the CFTR channel may function without consuming a large amount of energy.”

The UI study may also have broad implications beyond CFTR. CFTR is a member of the ABC transporter family, the largest group of proteins that move molecules across membranes. These proteins exist in all forms of life and they transfer a very diverse group of molecules across membranes.

ABC transporters are involved in many genetic diseases, and they are significant targets for therapeutics. Therefore, it will now be important to investigate whether other ABC transporters are also adenylate kinases. If they are, the adenylate kinase activity could provide a novel way to modulate their actions.

“ABC transporter proteins contain a very conserved ’engine’ that controls transport,” Randak said. “Our study indicates that at least in CFTR that ’engine’ can be run either by an ATPase, which uses energy, or an adenylate kinase, which is energy-neutral.”

Randak’s co-author for the study was Michael J. Welsh, M.D., Howard Hughes Medical Institute (HHMI) Investigator, and the Roy J. Carver Chair of Biomedical Research in the UI Departments of Internal Medicine and Physiology and Biophysics.

The study was funded in part by grants from the National Heart, Lung and Blood Institute, one of the National Institutes of Health, and the Forschungsgemeinschaft, a German grant-awarding organization.

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STORY SOURCE: University of Iowa Health Science Relations, 5135 Westlawn, Iowa City, Iowa 52242-1178

CONTACT(S): Jennifer Brown, 319-335-9917, jennifer-l-brown@uiowa.edu