By constructing a mutated protein through genetic engineering,scientists have come closer to understanding the defect incystic fibrosis.

Naturally occurring human mutations that cause the diseaseaffect a pore molecule that sits in cell surfaces and changesthe flow of ions across the cell membrane. Scientists atGenzyme Corp. of Framingham, Mass., and universitycollaborators specifically introduced mutations in the poremolecule. By changing the amino acids lining the pore, thesemutations altered the conductance of ions such as chloride andiodide through the pore.

The results show that the pore protein, called cystic fibrosistransmembrane conductance regulator, serves as a chloridechannel, the scientists concluded in their report Friday inScience. The research team included scientists from theUniversity of Iowa medical school and the MassachusettsInstitute of Technology.

Chloride transport is abnormal in the cells of people withcystic fibrosis; the ion pores do not open in response to thecell messenger, cyclic AMP. Without proper ion flow,secretions from cells become too thick and sticky.

To probe the pore's structure further, the researchers alsoaltered the protein's major structural features. A version ofthe pore missing a segment called the R domain conducted ionswithout first requiring a signal from cyclic AMP.

But the R domain only partly explains the pore's dependence oncyclic AMP, the researchers concluded. They propose a model ofthe pore molecule in which the R domain keeps the ion channelclosed and suggest that one of the two portions of themolecule that bind nucleotides interacts with the R domain tohelp control the channel.

-- Roberta Friedman, Ph.D. Special to BioWorld

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