Benzo(c)quinolizinium drugs inhibit degradation of ΔF508-CFTR cytoplasmic domain
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- 作者：Stratford ; Fiona L.L. ; Pereira ; Malcolm M.C. ; Becq ; Frederic ; McPherson ; Margaret A. ; Dormer ; Robert L.
- 关键词：Cystic fibrosis transmembrane conductance regulator protein ; Cytoplasmic domain ; Δ ; F508 mutation ; Degradation ; Cysteine protease ; Benzo(c)quinolizinium compounds
- 刊名：Biochemical and Biophysical Research Communications
- 出版年：2003
- 出版时间：January 10, 2003
- 年：2003
- 卷：300
- 期：2
- 页码：524-530
- 全文大小：208 K
文摘
Proteins comprising the first nucleotide-binding- and R-domains of wild-type and ΔF508 cystic fibrosis transmembrane conductance regulator (CFTR) have been synthesised by in vitro transcription/translation. The kinetics and extent of degradation of wild-type and ΔF508 cytoplasmic domain proteins in rabbit reticulocyte lysates, in which proteasome activity was inhibited, were similar, with a half-life of approximately 4h. The results show for the first time, that the benzo(c)quinolizinium compounds, MPB-07 and MPB-91, selectively inhibit degradation of the ΔF508 cytoplasmic domain protein. Studies using protease inhibitors demonstrated that both ΔF508 and wild-type proteins are substrates for cysteine proteases. The studies provide evidence that benzo(c)quinolizinium compounds protect a proteolytic cleavage site by direct binding to the first cytoplasmic domain of ΔF508-CFTR and this is a likely mechanism for increasing ΔF508-CFTR trafficking in intact cells.