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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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Regulation of the Unfolded Protein Response01:31

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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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The Unfolded Protein Response01:37

The Unfolded Protein Response

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The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
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Chromatin Structure Regulates pre-mRNA Processing02:41

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In eukaryotic cells, nascent mRNA transcripts need to undergo many post-transcriptional modifications to reach the cell cytoplasm and translate into functional proteins. For a long time, transcription and pre-mRNA processing were considered two independent events that occur sequentially in the cell. However, it has now been well established that transcription and pre-mRNA processing are two simultaneous processes that are precisely regulated inside the cell.
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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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Coat Assembly and GTPases01:33

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Vesicles incorporate different coat protein subunits in different cell locations, which changes the properties of the coat, such as the shape and geometry of the transport vesicles. Thus, vesicle coat proteins also play a significant role in cargo selection.
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Related Experiment Video

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Studies of Chaperone-Cochaperone Interactions using Homogenous Bead-Based Assay
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Hsp90 and cochaperones have two genetically distinct roles in regulating eEF2 function.

Melody D Fulton1, Danielle J Yama1, Ella Dahl1

  • 1Department of Biological Sciences, University of Idaho, Moscow, Idaho, United States of America.

Plos Genetics
|December 9, 2024
PubMed
Summary
This summary is machine-generated.

Heat shock protein 90 (Hsp90) and its cochaperones regulate eukaryotic elongation factor 2 (eEF2) for protein homeostasis. They impact both protein folding and accurate translation, with distinct roles affecting eEF2 levels and function.

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In Situ Monitoring of Transiently Formed Molecular Chaperone Assemblies in Bacteria, Yeast, and Human Cells
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Area of Science:

  • Molecular Biology
  • Protein Homeostasis
  • Cellular Stress Response

Background:

  • Protein homeostasis is crucial for cell function, relying on accurate protein synthesis and folding.
  • Eukaryotic elongation factor 2 (eEF2) is essential for ribosomal translocation during translation.
  • Hsp90 chaperone machinery, including cochaperones like Hgh1, Cns1, and Cpr7, is known to assist eEF2 folding.

Purpose of the Study:

  • To investigate the distinct roles of Hsp90 and its cochaperones in regulating eEF2 function.
  • To determine how Hsp90 and cochaperone mutations affect eEF2 levels, folding, and translation activity.
  • To explore the link between Hsp90/cochaperone function, eEF2 post-translational modifications, and cellular phenotypes.

Main Methods:

  • Analysis of yeast strains expressing various Hsp90 and cochaperone mutations.
  • Measurement of steady-state eEF2 levels in mutant strains.
  • Assessment of growth phenotypes and sensitivity to diphtheria toxin in relation to eEF2 function.

Main Results:

  • Specific Hsp90 and cochaperone mutations led to reduced eEF2 protein levels.
  • Loss of Hgh1 exacerbated growth defects in Hsp90 mutants affecting eEF2 accumulation.
  • Mutations mimicking human disease-associated eEF2 defects were sensitive to Hgh1 loss, with some rescue by Hgh1 overexpression.
  • Distinct Hsp90/cochaperone mutations altered eEF2 post-translational modification, impacting diphtheria toxin sensitivity.

Conclusions:

  • Hsp90 and cochaperones play dual roles in maintaining proteostasis: facilitating protein folding and ensuring accurate translation.
  • Yeast Hsp90 mutants exhibit distinct in vivo effects, correlating with defects in specific cochaperone subsets.
  • These findings highlight the complex regulatory network governing eEF2 function and its impact on cellular processes.