Perturbation of sodium channel structure by an inherited Long QT Syndrome mutation

被引:22
作者
Glaaser, Ian W. [1 ]
Osteen, Jeremiah D. [1 ]
Puckerin, Akil [1 ]
Sampson, Kevin J. [1 ]
Jin, Xiangshu [2 ,3 ]
Kass, Robert S. [1 ]
机构
[1] Columbia Univ, Med Ctr, Dept Pharmacol, Coll Phys & Surg, New York, NY 10032 USA
[2] Columbia Univ, Med Ctr, Dept Biochem & Mol Biophys, New York, NY 10032 USA
[3] Howard Hughes Med Inst, New York, NY 10032 USA
基金
美国国家卫生研究院;
关键词
HYPERKALEMIC PERIODIC PARALYSIS; SOLUTION NMR STRUCTURE; CARDIAC NA+ CHANNEL; EF-HAND DOMAIN; INACTIVATION GATE; CALMODULIN; CALCIUM; COMPLEX; IDENTIFICATION; ARRHYTHMIA;
D O I
10.1038/ncomms1717
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The cardiac voltage-gated sodium channel (Na(V)1.5) underlies impulse conduction in the heart, and its depolarization-induced inactivation is essential in control of the duration of the QT interval of the electrocardiogram. Perturbation of Na(V)1.5 inactivation by drugs or inherited mutation can underlie and trigger cardiac arrhythmias. The carboxy terminus has an important role in channel inactivation, but complete structural information on its predicted structural domain is unknown. Here we measure interactions between the functionally critical distal carboxy terminus alpha-helix (H6) and the proximal structured EF-hand motif using transition-metal ion fluorescence resonance energy transfer. We measure distances at three loci along H6 relative to an intrinsic tryptophan, demonstrating the proximal-distal interaction in a contiguous carboxy terminus polypeptide. Using these data together with the existing Na(V)1.5 carboxy terminus nuclear magnetic resonance structure, we construct a model of the predicted structured region of the carboxy terminus. An arrhythmia-associated H6 mutant that impairs inactivation decreases fluorescence resonance energy transfer, indicating destabilization of the distal-proximal intramolecular interaction. These data provide a structural correlation to the pathological phenotype of the mutant channel.
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页数:8
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