Press releases
Please quote Nature Structural & Molecular Biology as the source of these items.
The January 2005 issue of Nature Structural & Molecular Biology is available online.
January 2005
The underlying causes of cystic fibrosis
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.
Side chain and backbone contributions of Phe508 to CFTR folding
Patrick H Thibodeau, Chad A Brautigam, Mischa Machius & Philip J Thomas
Published online: 26 December 2004 | doi 10.1038/nsmb881
The ΔF508 cystic fibrosis mutation impairs domain-domain interactions and arrests post-translational folding of CFTR
Kai Du, Manu Sharma & Gergely L Lukacs
Published online: 26 December 2004 | doi 10.1038/nsmb882
