A single mutation in the cystic fibrosis protein causes defects at two distinct stages in its maturation process, leading to cystic fibrosis. These findings, reported in two complementary studies in the January issue of Nature Structural & Molecular Biology, will impact the design of treatment for this devastating disease.
Cystic fibrosis is an inherited disease affecting approximately 30,000 people in the US alone, with the Caucasian population particularly at risk. The disease results from mutations in a chloride channel, called CFTR or cystic fibrosis transmembrane conductance regulator. CFTR is made up of around 1400 amino acids organized into several structural units. These structural units assemble into a functional channel, regulating and transporting chloride ions from the cell. In cystic fibrosis patients, the most common disease causing-mutation is a single deletion of one amino acid at position 508. This mutation disrupts the maturation process of CFTR, causing premature degradation of the protein and the loss of crucial channel activity in lung cells. The end result is clogged airways with thick, sticky mucus.
Thomas and colleagues and Lukacs and colleagues now provide evidence that the main chain and side chain of amino acid 508 play different roles in the maturation process of CFTR. The loss of the main chain disrupts the folding of the structural unit that normally contains amino acid 508, whereas the loss of the side chain disrupts the assembly of two structural units within CFTR. These observations suggest that effective cystic fibrosis treatments designed to assist the correct folding of CFTR will need to overcome the defects at both stages of the process, therefore requiring a two-pronged attack.
Philip J. Thomas (University of Texas Southwestern Medical Center, Dallas, TX, USA)
Tel: +1 214 648 8723, E-mail: Philip.Thomas@UTSouthwestern.edu
Gergley Lukacs (Hospital for Sick Children, Toronto, Canada)
Tel: +1 416 813 5125, E-mail: firstname.lastname@example.org
Douglas Cyr (University of North Carolina at Chapel Hill, NC, USA)
Tel: +1 919 843 4805, E-mail: email@example.com
Also available online (click on links):study 1, and study 2.
(C) Nature Structural & Molecular Biology press release.
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