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A protein's well-known cousin sheds light on its gout-linked relative
Date:4/8/2013

be remedied by dietary changes, about 10 percent of Caucasians get the disorder because their ABCG2 protein contains the Q141K mutation. This number is lower (around 3 percent) for African-Americans and much higher (31 percent) for Asians.

Guggino notes that the ABCG2 Q141K mutation was first connected with gout in 2008 through a large genomic study directed, in part, by Josef Coresh, M.D., a biostatistician and epidemiologist at the Johns Hopkins University School of Public Health. At the time, Guggino's laboratory was studying a protein frequently found mutated in cystic fibrosis patients: cystic fibrosis transmembrane conductance regulator, or CFTR. The structure of ABCG2 is quite similar to CFTR's, so Coresh suggested that Guggino's team apply their knowledge of CFTR to characterize ABCG2.

The team first genetically engineered several standard mammalian cell types to make regular or mutant versions of ABCG2. Cells with the mutated ABCG2 gene contained much less of the ABCG2 protein than cells making the regular form. Additionally, the researchers found that the mutation made it difficult for ABCG2 molecules to get to their proper place on the cell surface. Since ABCG2 pumps molecules from the inside of the cell to the outside, it is not functional anywhere but the cell surface.

The team then lowered the temperature at which the ABCG2-making cells were growing, and found more mutant ABCG2 at the cell surface. Guggino says this finding suggested that the lower temperature had stabilized ABCG2 and helped it achieve its proper 3-D conformation, because proteins that don't assume the right shape are likely to be broken into pieces for reuse, preventing them from reaching their final destinations.

When ABCG2 and CFTR are lined up, their structures are very similar. In fact, one of the most common cystic fibrosis mutations, a CFTR deletion of amino acid F508, lines up next to the Q141K mutation in ABCG2 and causes similar results in
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Contact: Catherine Kolf
ckolf@jhmi.edu
443-287-2251
Johns Hopkins Medicine
Source:Eurekalert

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