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- W4377029282 abstract "<b>Abstract ID 15966</b> <b>Poster Board 88</b> Phospholipase Ce enzymes are required for normal cardiovascular function, and their dysregulation can lead to cardiac hypertrophy and heart failure. PLCe cleaves phosphatidylinositol phosphates into inositol phosphates and diacylglycerol, increasing intracellular Ca<sup>2+ </sup>and activating protein kinase C. PLCe activity is increased by direct binding of the Rap1A GTPase, following stimulation of b-adrenergic receptors. This pathway is required for maximum cardiac contractility, but sustained activation causes cardiac hypertrophy. Rap1A binds to the C-terminal Ras Association (RA) domain of PLCe, and we previously showed that activation requires long-range conformational changes in the lipase. However, the residues in PLCe involved in the intramolecular rearrangements are not known. As a first step, I used cryo-electron microscopy single particle analysis (cryo-EM SPA) to determine the 4 Å reconstruction of PLCe PH-C in complex with an antigen binding fragment (Fab). This is the largest fragment of PLCe biochemically characterized to date and is robustly activated by Rap1A. The structure defines the basal state of the enzyme and reveals a potential membrane binding surface on the PH domain. These studies set the stage for investigating the structure of the Rap1A–PLCe PH-C complex and its mechanism of activation. Ultimately, this work supports long-term efforts to develop small molecule modulators of the lipase and its activated complex for treating cardiac hypertrophy." @default.
- W4377029282 created "2023-05-19" @default.
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- W4377029282 date "2023-05-18" @default.
- W4377029282 modified "2023-09-29" @default.
- W4377029282 title "Mechanistic insights into Rap1A-dependent regulation of phospholipase C epsilon in the heart" @default.
- W4377029282 doi "https://doi.org/10.1124/jpet.122.159660" @default.
- W4377029282 hasPublicationYear "2023" @default.
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