Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 11, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2100069118
Keywords
Na(v)1.5; long QT syndrome; Brugada syndrome; fast inactivation; structure-function relationship
Categories
Funding
- National Key R&D Program from the Ministry of Science and Technology of China [2016YFA0500402]
- Beijing Nova Program from the Beijing Municipal Science and Technology Commission [Z191100001119127]
- Princeton University
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Na(v)1.5 is the primary voltage-gated Na+ channel in the heart, mutations of which are associated with various cardiac disorders. The study reveals the structural distribution of mutations associated with LQT3 and BrS, with a focus on a mutational hotspot involving the fast inactivation segments and proposing a door wedge model for fast inactivation. This structural analysis establishes a structure-function relationship for understanding the mechanistic of Na(v)1.5 channelopathies.
Na(v)1.5 is the primary voltage-gated Na+ (Na-v) channel in the heart. Mutations of Na(v)1.5 are associated with various cardiac disorders exemplified by the type 3 long QT syndrome (LQT3) and Brugada syndrome (BrS). E1784K is a common mutation that has been found in both LQT3 and BrS patients. Here we present the cryo-EM structure of the human Na(v)1.5-E1784K variant at an overall resolution of 3.3 angstrom. The structure is nearly identical to that of the wild-type human Na(v)1.5 bound to quinidine. Structural mapping of 91- and 178-point mutations that are respectively associated with LQT3 and BrS reveals a unique distribution pattern for LQT3 mutations. Whereas the BrS mutations spread evenly on the structure, LQT3 mutations are clustered mainly to the segments in repeats III and IV that are involved in gating, voltage-sensing, and particularly inactivation. A mutational hotspot involving the fast inactivation segments is identified and can be mechanistically interpreted by our door wedge model for fast inactivation. The structural analysis presented here, with a focus on the impact of mutations on inactivation and late sodium current, establishes a structure-function relationship for the mechanistic understanding of Na(v)1.5 channelopathies.
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