Related Experiment Video
Updated: Jul 31, 2025
07:18
Intracellular Refolding Assay
Published on: January 24, 2012
14.2K
Mechanisms of Protein Quality Control in the Endoplasmic Reticulum by a Coordinated Hsp40-Hsp70-Hsp90 System
Judy L M Kotler1, Timothy O Street1
1Department of Biochemistry, Brandeis University, Waltham, Massachusetts, USA;
Annual Review of Biophysics
|May 9, 2023
Summary
This review explores how heat shock protein (Hsp) 40, Hsp70, and Hsp90 chaperones cooperate to maintain protein homeostasis. We propose new hypotheses for client transfer benefits, including aggregate solubilization and protein degradation targeting.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Heat shock proteins (Hsp) 40, Hsp70, and Hsp90 are vital for cellular protein homeostasis.
- Client transfer between these chaperone families is observed but its functional significance remains unclear.
Purpose of the Study:
- To review mechanistic data on ERdj3 (Hsp40), BiP (Hsp70), and Grp94 (Hsp90) function within the endoplasmic reticulum.
- To explore how these chaperones may work together as a unified system.
- To propose and examine hypotheses for the functional benefits of client transfer among Hsp40, Hsp70, and Hsp90.
Main Methods:
- Compilation of existing mechanistic data on ERdj3, BiP, and Grp94.
- Computational analysis to examine the impact of client transfer on protein folding, aggregate solubilization, and degradation.
- Discussion of potential experimental approaches to test proposed hypotheses.
Main Results:
- The review compiles current knowledge on the interplay between ERdj3, BiP, and Grp94.
- Computational analysis suggests client transfer impacts protein aggregate solubilization, soluble protein folding, and protein triage for degradation.
- New hypotheses regarding the functional roles of client transfer are proposed.
Conclusions:
- Understanding the coordinated action of Hsp40, Hsp70, and Hsp90 is crucial for comprehending protein homeostasis.
- Client transfer between these chaperones likely confers significant functional advantages.
- Further experimental validation is needed to confirm the proposed roles of client transfer in protein processing and quality control.
Related Concept Videos
01:29Protein Folding Quality Check in the RER
3.8K
ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
3.8K
01:32Export of Misfolded Proteins out of the ER
3.7K
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...
3.7K
01:37The Unfolded Protein Response
4.8K
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...
4.8K
01:31Regulation of the Unfolded Protein Response
2.5K
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...
2.5K
03:00Molecular Chaperones and Protein Folding
18.1K
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.
The...
The...
18.1K
01:26Bacterial Protein Maturation
43
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...
43