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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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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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The Unfolded Protein Response01:37

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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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It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
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The Proteasome01:13

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Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
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Intracellular Refolding Assay
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Cellular sequestrases maintain basal Hsp70 capacity ensuring balanced proteostasis.

Chi-Ting Ho1,2, Tomas Grousl1,2,3, Oren Shatz1,2

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Cellular protein quality control uses sequestration to prevent proteostasis collapse. Sequestrases Hsp42 and Btn2 shield Hsp70, aiding refolding and cell viability during stress.

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Area of Science:

  • Cellular Biology
  • Biochemistry
  • Molecular Biology

Background:

  • Cellular proteostasis relies on refolding and degradation to manage misfolded proteins.
  • Organized sequestration of misfolded proteins by sequestrases is an emerging quality control strategy.
  • Understanding sequestration's role is crucial for comprehending the overall proteostasis network.

Purpose of the Study:

  • To elucidate the role of protein sequestration in the proteostasis network of Saccharomyces cerevisiae.
  • To investigate the underlying mechanisms of protein sequestration.
  • To determine the interplay between sequestrases and the Hsp70 refolding system.

Main Methods:

  • Investigated the function of Hsp42 and Btn2 sequestrases in Saccharomyces cerevisiae.
  • Examined the interaction between sequestrases and the Hsp70 chaperone system.
  • Assessed the impact of sequestration on proteostasis collapse and cell viability under stress conditions.

Main Results:

  • Hsp42 and Btn2 sequestrases are functionally linked to the Hsp70 refolding machinery.
  • Sequestration by Hsp42 and Btn2 prevents proteostasis collapse and loss of viability when Hsp70 capacity is limited.
  • Btn2 exhibits both chaperone and sequestrase activity, resembling small heat shock proteins, and facilitates the recruitment of the Hsp70-Hsp104 disaggregase via Sis1 interaction during stress recovery.

Conclusions:

  • Sequestration is a vital third strategy for maintaining cellular proteostasis, complementing refolding and degradation.
  • Hsp42 and Btn2 protect the Hsp70 system from overload, ensuring cell survival under stress.
  • Btn2 plays a key role in directing sequestered proteins back to the refolding pathway during stress recovery.