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Upgraded molecular models of the human KCNQ1 potassium channel


Autoři: Georg Kuenze aff001;  Amanda M. Duran aff001;  Hope Woods aff001;  Kathryn R. Brewer aff001;  Eli Fritz McDonald aff001;  Carlos G. Vanoye aff004;  Alfred L. George, Jr. aff004;  Charles R. Sanders aff001;  Jens Meiler aff001
Působiště autorů: Center for Structural Biology, Vanderbilt University, Nashville, Tennessee, United States of America aff001;  Department of Chemistry, Vanderbilt University, Nashville, Tennessee, United States of America aff002;  Department of Biochemistry, Vanderbilt University, Nashville, Tennessee, United States of America aff003;  Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America aff004;  Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, United States of America aff005
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0220415

Souhrn

The voltage-gated potassium channel KCNQ1 (KV7.1) assembles with the KCNE1 accessory protein to generate the slow delayed rectifier current, IKS, which is critical for membrane repolarization as part of the cardiac action potential. Loss-of-function (LOF) mutations in KCNQ1 are the most common cause of congenital long QT syndrome (LQTS), type 1 LQTS, an inherited genetic predisposition to cardiac arrhythmia and sudden cardiac death. A detailed structural understanding of KCNQ1 is needed to elucidate the molecular basis for KCNQ1 LOF in disease and to enable structure-guided design of new anti-arrhythmic drugs. In this work, advanced structural models of human KCNQ1 in the resting/closed and activated/open states were developed by Rosetta homology modeling guided by newly available experimentally-based templates: X. leavis KCNQ1 and various resting voltage sensor structures. Using molecular dynamics (MD) simulations, the capacity of the models to describe experimentally established channel properties including state-dependent voltage sensor gating charge interactions and pore conformations, PIP2 binding sites, and voltage sensor–pore domain interactions were validated. Rosetta energy calculations were applied to assess the utility of each model in interpreting mutation-evoked KCNQ1 dysfunction by predicting the change in protein thermodynamic stability for 50 experimentally characterized KCNQ1 variants with mutations located in the voltage-sensing domain. Energetic destabilization was successfully predicted for folding-defective KCNQ1 LOF mutants whereas wild type-like mutants exhibited no significant energetic frustrations, which supports growing evidence that mutation-induced protein destabilization is an especially common cause of KCNQ1 dysfunction. The new KCNQ1 Rosetta models provide helpful tools in the study of the structural basis for KCNQ1 function and can be used to generate hypotheses to explain KCNQ1 dysfunction.

Klíčová slova:

Biology and life sciences – Biochemistry – Computational biology – Physical sciences – Chemistry – Research and analysis methods – Proteins – Molecular biology – Macromolecular structure analysis – Database and informatics methods – Bioinformatics – Sequence analysis – Sequence alignment – Neuroscience – Simulation and modeling – Medicine and health sciences – Physiology – Lipids – Physics – Biological databases – Electrophysiology – Neurophysiology – Biophysics – Microscopy – Physical chemistry – Electron microscopy – Electron cryo-microscopy – Protein structure databases – Biochemical simulations – Protein structure – Chemical bonding – Hydrogen bonding


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