Metal Bridges Illuminate Transmembrane Domain Movements During Gating of the Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel [Molecular Biophysics]

August 20th, 2014 by El Hiani, Y., Linsdell, P.

Opening and closing of the cystic fibrosis transmembrane conductance regulator is controlled by ATP binding and hydrolysis by the cytoplasmic nucleotide binding domains. Different conformational changes in the channel pore have been described during channel opening and closing, however, the relative importance of these changes to the process of gating the pore is not known. We have used patch clamp recording to identify high affinity Cd2+ bridges formed between pairs of pore-lining cysteine residues introduced into different transmembrane α-helices (TMs). Seven Cd2+ bridges were identified forming between cysteines in TM6 and TM12. Interestingly, each of these Cd2+ bridges apparently formed only in closed channels, and their formation stabilized the closed state. In contrast, a single Cd2+ bridge identified between cysteines in TM1 and TM12 stabilized the channel open state. Analysis of the pattern of Cd2+ bridge formation in different channel states suggests that lateral separation and convergence of different TMs, rather than relative rotation or translation of different TMs, is the key conformational change that causes the channel pore to open and close.
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