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Cryo-electron tomography reveals the structural diversity of cardiac proteins in their cellular context.


ABSTRACT: Cardiovascular diseases are a leading cause of death worldwide, but our understanding of the underlying mechanisms is limited, in part because of the complexity of the cellular machinery that controls the heart muscle contraction cycle. Cryogenic electron tomography (cryo-ET) provides a way to visualize diverse cellular machinery while preserving contextual information like subcellular localization and transient complex formation, but this approach has not been widely applied to the study of heart muscle cells (cardiomyocytes). Here, we deploy a platform for studying cardiovascular disease by combining cryo-ET with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). After developing a cryo-ET workflow for visualizing macromolecules in hiPSC-CMs, we reconstructed sub-nanometer resolution structures of the human thin filament, a central component of the contractile machinery. We also visualized a previously unobserved organization of a regulatory complex that connects muscle contraction to calcium signaling (the troponin complex), highlighting the value of our approach for interrogating the structures of cardiac proteins in their cellular context.

SUBMITTER: Woldeyes RA 

PROVIDER: S-EPMC10634850 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Structure of the Thin Filament in Human iPSC-derived Cardiomyocytes and its Response to Heart Disease.

Woldeyes Rahel A RA   Nishiga Masataka M   Roest Alison S Vander ASV   Engel Leeya L   Giri Prerna P   Montenegro Gabrielle C GC   Dunn Alexander R AR   Spudich James A JA   Bernstein Daniel D   Schmid Michael F MF   Wu Joseph C JC   Chiu Wah W  

bioRxiv : the preprint server for biology 20250223


Cardiovascular diseases are a leading cause of death worldwide, but our understanding of the underlying mechanisms is limited, in part because of the complexity of the cellular machinery that controls the heart muscle contraction cycle. Cryogenic electron tomography (cryo-ET) provides a way to visualize diverse cellular machinery while preserving contextual information like subcellular localization and transient complex formation, but this approach has not been widely applied to the study of hea  ...[more]

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