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About Sickkids
About SickKids

January 9, 2007

One step closer to understanding the cause of cystic fibrosis

Researchers at SickKids have discovered some of the underlying causes of cystic fibrosis at the molecular level. Deletion of a single amino acid, the most common cause of cystic fibrosis, results in the defect of the cystic fibrosis protein maturation and manifests in cystic fibrosis. These findings are reported in the January issue of Nature Structural & Molecular Biology.

The cystic fibrosis protein, CFTR, which is made up of more than 1400 amino acids, is organized into five structural units or "domains". Delicate interactions between these domains of CFTR ensure the normal ion and water movement across the cell surface in lung cells. The most common disease causing-mutation in cystic fibrosis patients is a single amino acid deletion at position 508 in the amino acid chain of CFTR. It was thought that this mutation disrupted the architecture of the first domain, where the 508 amino acid is localized and thereby prevented the protein from appearing at cell surface.

SickKids Senior Scientist Gergely Lukacs and his colleagues have shown that the architectural maturation of CFTR domains occurs in sequential manner in the cell. Surprisingly, they also demonstrated that the infamous 508 amino acid is essential for the structural maturation and stability of a second domain, but not the first one, where the 508 amino acid is localized. "Since the first domain serves as scaffold for the structural maturation of the second one, the three dimensional architecture of the first domain, including the 508 amino acid, is key for the global folding of CFTR" says Lukacs, who is also an Associate Professor in the Department of Laboratory Medicine & Pathobiology and Surgery at the University of Toronto. "Our data suggest an intricate interaction between the first and second domain of CFTR and that the loss of the 508 amino acid has devastating consequences on the structure of the second domain. Cellular mechanisms can recognize the abnormal domain structure and target the mutant CFTR for premature degradation."

The group efforts now focus on understanding the impact of other mutations on domain-domain interactions in CFTR. Using novel screening assays, they also participates in collaborative efforts to identify small molecules as potential drugs that will rescue the folding defect of mutant CFTR.

The research was supported by the Canadian Cystic Fibrosis Foundation,the Canadian Institutes of Health Research and SickKids Foundation.


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The Hospital for Sick Children