Effect of Potentiator VX-770 on the Kinetics of Disease-Associated Mutant CFTR Channels

POSTER

Abstract

CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) is a Cl- channel whose malfunction results in the genetic disease CF. One of the most common CF-associated mutations is the deletion of Phe 508 ($\Delta$F508) resulting in channels with poor membrane expression and impaired function. Several functional abnormalities were demonstrated: infrequent openings, shorter locked-open time, reduced resident-time for the ATP molecule bound in the first nucleotide binding domain NBD1. Recently, the drug VX-770 was approved for clinical use, which increases the activity of $\Delta$F508-CFTR. We studied the effect of VX-770 on the functional defects associated with $\Delta$F508-CFTR: the Po of the channels is increased 12x due to the increase of opening rate and open time. Response to ATP analogues is decreased when channels are treated in conjunction with VX-770, suggesting that the potentiator by itself repairs gating defects. The potentiation effect was observed for temperature-corrected channels as well as channels treated with corrector VX-809. The shorter locked-open time of hydrolysis-deficient mutants is prolonged by VX-770 suggesting a stabilizing effect on the NBD dimer. The ATP resident time at NBD1, reflecting a partial NBD dimer configuration, is not affected by VX-770.

Authors

  • Zuleyha Yuksek

    University of Missouri

  • Mark Neubauer

    University of Missouri-Columbia, Southern Illinois University Carbondale, Indiana University, Purdue University, Argonne National Laboratory, University of Missouri, College of Physics Science, Qingda University, Qingdao, 266071, China, Indian Institute of Science, Bangalore, India, University of Massachusetts Amherst, Iowa State University, Technical University of Denmark, University of Missouri - Columbia, University of California - San Diego, La Jolla, CA 92093, Department of Physics, University of Missouri-Columbia, Columbia, Missouri 65211, Department of Physics and Astronomy, University of Missouri-Columbia, University of Missouri, Columbia, MO, Department of Physics and Department of Biochemistry, University of Missouri, Columbia, MO 65211, Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599-3290, Univ of Missouri - Columbia, Duke University, Shanghai Jiaotong University, Ames Laboratory, U.S. DOE, Texas Center of Superconductivity and the Department of Physics, University of Houston, Institute of Physics, Siberian Division, Russian Academy of Sciences, Krasnoyarsk, 66036, Russia, Oak Ridge National Laboratory, NIST Center for Neutron Research, MU Research Reactor, Ames Laboratory and Dep. of Physics and Astronomy, Iowa State University, AmesAmes Laboratory and Dep. of Physics and Astronomy, Iowa State University, HFIR, Oak Ridge National Laboratory, University of Illinois at Urbana-Champaign

  • Silvia Bompadre

    University of Missouri