A stable ATP binding to the nucleotide binding domain is important for reliable gating cycle in an ABC transporter CFTR.

The Journal of Physiological Sciences : JPS
Hiroyasu ShimizuYoshiro Sohma

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) anion channel, a member of ABC transporter superfamily, gates following ATP-dependent conformational changes of the nucleotide binding domains (NBD). Reflecting the hundreds of milliseconds duration of the channel open state corresponding to the dimerization of two NBDs, macroscopic WT-CFTR currents usually showed a fast, single exponential relaxation upon removal of cytoplasmic ATP. Mutations of tyrosine1219, a residue critical for ATP binding in second NBD (NBD2), induced a significant slow phase in the current relaxation, suggesting that weakening ATP binding affinity at NBD2 increases the probability of the stable open state. The slow phase was effectively diminished by a higher affinity ATP analogue. These data suggest that a stable binding of ATP to NBD2 is required for normal CFTR gating cycle, andthat the instability of ATP binding frequently halts the gating cycle in the open state presumably through a failure of ATP hydrolysis at NBD2.

References

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Citations

Apr 5, 2011·The Journal of Physiological Sciences : JPS·Oleg V KrasilnikovYasunobu Okada
Aug 28, 2013·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Peter Prehm
Jun 29, 2018·The Journal of Physiological Sciences : JPS·Kanako Wakabayashi-NakaoYoshiro Sohma

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