An Unbiased Screen Identified the Hsp70-BAG3 Complex as a Regulator of Myosin-Binding Protein C3

Variants in the gene myosin-binding protein C3 (MYBPC3) account for approximately 50% of familial hypertrophic cardiomyopathy (HCM), leading to reduced levels of myosin-binding protein C3 (MyBP-C), the protein product made by gene MYBPC3. Elucidation of the pathways that regulate MyBP-C protein home...

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Detalles Bibliográficos
Autores principales: Thompson, Andrea D., Wagner, Marcus J., Rodriguez, Juliani, Malhotra, Alok, Vander Roest, Steve, Lilienthal, Ulla, Shao, Hao, Vignesh, Mathav, Weber, Keely, Yob, Jaime M., Prosser, Benjamin L., Helms, Adam S., Gestwicki, Jason E., Ginsburg, David, Day, Sharlene M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Original Research - Preclinical
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10544073/
https://www.ncbi.nlm.nih.gov/pubmed/37791314
http://dx.doi.org/10.1016/j.jacbts.2023.04.009
Descripción
Sumario:Variants in the gene myosin-binding protein C3 (MYBPC3) account for approximately 50% of familial hypertrophic cardiomyopathy (HCM), leading to reduced levels of myosin-binding protein C3 (MyBP-C), the protein product made by gene MYBPC3. Elucidation of the pathways that regulate MyBP-C protein homeostasis could uncover new therapeutic strategies. Toward this goal, we screened a library of 2,426 bioactive compounds and identified JG98, an allosteric modulator of heat shock protein 70 that inhibits interaction with Bcl-2–associated athanogene (BAG) domain co-chaperones. JG98 reduces MyBP-C protein levels. Furthermore, genetic reduction of BAG3 phenocopies treatment with JG-98 by reducing MYBP-C protein levels.. Thus, an unbiased compound screen identified the heat shock protein 70–BAG3 complex as a regulator of MyBP-C stability.

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