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Allosteric Mechanisms Underlying Long QT Syndrome Type 2 (LQT2)-Associated Mutations in hERG Channels
Audrey Deyawe Kongmeneck1, Geraldine San Ramon1, Brian Delisle2
1Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.
Biorxiv : the Preprint Server for Biology
|April 17, 2026
Summary
Long QT syndrome Type 2 (LQT2) arises from KCNH2 gene mutations. These mutations disrupt potassium channel (KV11.1) trafficking by altering the selectivity filter structure, impacting heart function.
Area of Science:
- Molecular biology
- Biophysics
- Cardiology
Background:
- Long QT syndrome Type 2 (LQT2) is a genetic disorder linked to KCNH2 gene mutations.
- Most LQT2-associated KV11.1 potassium channel mutations cause loss-of-function due to impaired trafficking.
- The structural basis for this trafficking defect remains incompletely understood.
Purpose of the Study:
- To investigate the molecular mechanisms by which KCNH2 missense mutations affect KV11.1 channel trafficking.
- To analyze the structural and dynamic differences between wild-type and mutant KV11.1 channels.
- To identify potential strategies for correcting trafficking defects.
Main Methods:
- Molecular dynamics (MD) simulations were employed to analyze wild-type and mutant KV11.1 channel structures.
- Simulations focused on conformational and dynamic changes, particularly within the selectivity filter (SF).
- The effects of disease-associated missense mutations on channel structure and dynamics were assessed.
Main Results:
- Missense mutations in the S4 helix were found to allosterically disrupt the KV11.1 selectivity filter.
- Trafficking-competent mutants maintained a wild-type-like SF structure, while trafficking-deficient mutants showed significant SF structural perturbations.
- Second-site variants, such as Y652C, demonstrated potential to correct structural defects in mistrafficking variants.
Conclusions:
- LQT2-associated KCNH2 missense mutations impair KV11.1 channel trafficking by compromising the structural integrity of the selectivity filter.
- The selectivity filter is a critical determinant for proper KV11.1 channel trafficking.
- Targeting structural defects in the selectivity filter or utilizing second-site variants may offer therapeutic avenues for LQT2.
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