Structural analyses of human ryanodine receptor type 2 channels reveal the mechanisms for sudden cardiac death and treatment

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Abstract

Ryanodine receptor type 2 (RyR2) mutations have been linked to an inherited form of exercise-induced sudden cardiac death called catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT results from stress-induced sarcoplasmic reticular Ca ²⁺ leak via the mutant RyR2 channels during diastole. We present atomic models of human wild-type (WT) RyR2 and the CPVT mutant RyR2-R2474S determined by cryo–electron microscopy with overall resolutions in the range of 2.6 to 3.6 Å, and reaching local resolutions of 2.25 Å, unprecedented for RyR2 channels. Under nonactivating conditions, the RyR2-R2474S channel is in a “primed” state between the closed and open states of WT RyR2, rendering it more sensitive to activation that results in stress-induced Ca ²⁺ leak. The Rycal drug ARM210 binds to RyR2-R2474S, reverting the primed state toward the closed state. Together, these studies provide a mechanism for CPVT and for the therapeutic actions of ARM210.

Abstract

Cryo-EM structures of human RyR2, pathological primed RyR2-R2474S, and RyR2-R2474S reveal a mechanism for Rycal ARM210 treatment.

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Author and article information

Contributors

Marco C. Miotto:

ORCID: https://orcid.org/0000-0001-8851-4863

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Gunnar Weninger: Role: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: Writing - review & editing

Haikel Dridi:

ORCID: https://orcid.org/0000-0001-9533-7367

Role: ConceptualizationRole: Data curationRole: InvestigationRole: MethodologyRole: ResourcesRole: Visualization

Qi Yuan: Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - review & editing

Yang Liu:

ORCID: https://orcid.org/0000-0002-8343-4431

Role: Investigation

Anetta Wronska:

ORCID: https://orcid.org/0000-0003-2288-2596

Role: Formal analysisRole: Investigation

Zephan Melville:

ORCID: https://orcid.org/0000-0001-8962-2612

Role: MethodologyRole: Writing - review & editing

Leah Sittenfeld: Role: Investigation

Steven Reiken:

ORCID: https://orcid.org/0000-0002-5807-3574

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - review & editing

Andrew R. Marks:

ORCID: https://orcid.org/0000-0002-8057-1502

Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - review & editing

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): sciadv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: July 2022

Publication date (Electronic, pub): 20 July 2022

Volume: 8

Issue: 29

Electronic Location Identifier: eabo1272

Affiliations

[ ¹ ]Department of Physiology and Cellular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.

[ ² ]Clyde and Helen Wu Center for Molecular Cardiology, Columbia University, New York, NY, USA.

Author notes

[* ]Corresponding author. Email: arm42@ 123456cumc.columbia.edu

Author information

Marco C. Miotto https://orcid.org/0000-0001-8851-4863

Haikel Dridi https://orcid.org/0000-0001-9533-7367

Yang Liu https://orcid.org/0000-0002-8343-4431

Anetta Wronska https://orcid.org/0000-0003-2288-2596

Zephan Melville https://orcid.org/0000-0001-8962-2612

Steven Reiken https://orcid.org/0000-0002-5807-3574

Andrew R. Marks https://orcid.org/0000-0002-8057-1502

Article

Publisher ID: abo1272

DOI: 10.1126/sciadv.abo1272

PMC ID: 9299551

PubMed ID: 35857850

SO-VID: 0840f58e-cd45-447d-9109-fe5d3da592bb

Copyright © Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.