Cystic fibrosis (CF) is one of the most common genetic diseases, and the gene affected in CF was one of the first disease-associated genes to be cloned. However, we still know little about how the numerous mutations that cause CF actually affect the encoded protein and its activity.
In patients with CF, cells in certain organs (such as the lungs or pancreas) produce abnormally thick mucus resulting from the faulty transport of chloride across the cell membranes. Symptoms of the disease include persistent coughing and wheezing, lung infections, and salty-tasting skin, and death usually occurs in young adulthood.
CF is caused by mutations in a gene encoding a protein called the cystic fibrosis transmembrane conductance regulator (CFTR). The normal CFTR protein resides in the cell membrane, and it assumes a specific shape that allows it to transport chloride. The most common mutation in CFTR is a small deletion, but there are also over 80 point mutations (changes of a single nucleotide) that result in varying severities of CF. All of the disease-associated mutations seem to reduce or destroy the activity of the CFTR protein.
Now, in the July issue of Nature Structural Biology (Vol. 8, No. 7), Charles Deber and colleagues of the Hospital for Sick Children in Toronto, Canada suggest specifically how some of those mutations may wreak havoc within the structure of CFTR.
By working in test tubes in a simplified model system - a small section of CFTR that consists of two of the 'transmembrane' or membrane-spanning regions of the protein - these researchers have shown that one common mutation (which results in a valine to an aspartic acid change at position 232) causes a hydrogen bond to form between the two transmembrane regions. This hydrogen bond (a strong association between two amino acids) is an aberrant interaction that does not occur in the normal protein. This interaction is likely to affect the assembly or overall final shape of the protein, and thus the activity, of the CFTR protein.
Many of the other 80 or so mutations in CFTR are similar in their chemical nature (that is, they replace a hydrophobic amino acid with a polar amino acid), and thus they could also potentially form new hydrogen bonds between transmembrane regions of the protein. Therefore, these results may explain in part why so many different mutations result in CF.
Dr. Charles M. Deber
The Hospital for Sick Children
Division of Structural Biology & Biochemistry
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Telephone: 416 813 5924
Fax: 416 813 5005
(C) Nature Structural Biology press release.
Message posted by: Trevor M. D'Souza
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