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Related Concept Videos

Molecular Chaperones and Protein Folding03:00

Molecular Chaperones and Protein Folding

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The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
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Bacterial protein maturation is a tightly regulated process that ensures newly synthesized polypeptides achieve correct functional conformations. This maturation involves a series of modifications, folding events, and quality control steps, often assisted by specialized chaperone proteins.N-Terminal ModificationsThe maturation of bacterial polypeptides begins cotranslationally as the polypeptide exits the ribosome. The first amino acid, N-formylmethionine (fMet), is typically modified at the...
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Cardiomyopathy III: Hypertrophic Cardiomyopathy01:29

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Hypertrophic cardiomyopathy, or HCM, is an autosomal dominant genetic disorder characterized by asymmetric left ventricular hypertrophy without ventricular dilation. It is more common in men and is typically diagnosed in young, athletic adults.EtiologyHCM is primarily genetic and is caused by mutations in genes encoding sarcomeric proteins. Researchers have identified over 1400 mutations across at least 11 different genes. Among these, the most frequently occurring mutations are found in the...
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Export of Misfolded Proteins out of the ER01:32

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After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
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Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
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Defining Hsp33's Redox-regulated Chaperone Activity and Mapping Conformational Changes on Hsp33 Using Hydrogen-deuterium Exchange Mass Spectrometry
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A BAG3 chaperone complex maintains cardiomyocyte function during proteotoxic stress.

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Mutations in BAG3, a co-chaperone, cause heart failure. Human iPSC-derived cardiomyocytes with BAG3 loss-of-function showed impaired function and increased sensitivity to cardiotoxic drugs, establishing a disease model.

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Area of Science:

  • Cardiovascular Biology
  • Proteostasis and Disease
  • Stem Cell Biology

Background:

  • Molecular chaperones maintain proteome quality, and their dysfunction is linked to heart failure.
  • Mutations in BAG3, a co-chaperone, are associated with inherited and sporadic dilated cardiomyopathy, suggesting a loss-of-function mechanism.
  • Previous studies in mice did not fully recapitulate BAG3-associated cardiomyopathy, necessitating a human model.

Purpose of the Study:

  • To create and characterize a human cellular model of BAG3-associated cardiomyopathy using induced pluripotent stem cells (iPSCs).
  • To investigate the role of BAG3 in myofibril structure and function in human cardiomyocytes.
  • To explore the sensitivity of BAG3-deficient cardiomyocytes to cardiotoxic agents and identify therapeutic targets.

Main Methods:

  • Generation of an isogenic series of human iPSCs with BAG3 loss-of-function mutations.
  • Differentiation of iPSCs into iPSC-derived cardiomyocytes (iPS-CMs) for functional and structural analysis.
  • Affinity tagging of endogenous BAG3 and mass spectrometry proteomics to identify interacting partners.

Main Results:

  • Heterozygous BAG3 mutations in iPS-CMs led to reduced BAG3 protein expression, myofibril disorganization, and impaired contractile function.
  • BAG3-deficient iPS-CMs exhibited heightened sensitivity to proteasome inhibitor-induced cardiotoxicity.
  • Proteomic analysis identified key components of the BAG3-coordinated cardioprotective chaperone complex.

Conclusions:

  • Human iPSC-derived cardiomyocytes with BAG3 loss-of-function mutations provide a relevant model for studying BAG3 cardiomyopathy.
  • BAG3 plays a critical role in maintaining cardiomyocyte structure and function and protecting against drug-induced cardiotoxicity.
  • This model system offers a platform for evaluating protein quality control pathways as therapeutic targets and understanding drug susceptibility in cardiac diseases.