Correcting the Cystic Fibrosis Disease Mutant,A455E CFTR |
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| Authors: | Liudmila Cebotaru Daniele Rapino Valeriu Cebotaru William B. Guggino |
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| Affiliation: | 1. Department of Ophthalmology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America.; 2. Department of Physiology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America.; 3. Department of Medicine, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America.; National Center for Scientific Research Demokritos, Greece, |
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| Abstract: | Cystic fibrosis is caused by more than 1000 mutations, the most common being the ΔF508 mutation. These mutations have been divided into five classes [1], with ΔF508 CFTR in class II. Here we have studied the class V mutation A455E. We report that the mature and immature bands of A455E are rapidly degraded primarily by proteasomes; the short protein half-life of this mutant therefore resembles that of ΔF508 CFTR. A455E could be rescued by treatment of the cells with proteasome inhibitors. Furthermore, co-transfection of A455E with the truncation mutant Δ264 CFTR also rescued the mature C band, indicating that A455E can be rescued by transcomplementation. We found that Δ264 CFTR bound to A455E, forming a bimolecular complex. Treatment with the compound correctors C3 and C4 also rescued A455E. These results are significant because they show that although ΔF508 belongs to a different class than A455E, it can be rescued by the same strategies, offering therapeutic promise to patients with Class V mutations. |
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