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Structural basis of the unfolded protein response
Alexei Korennykh1, Peter Walter
1Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA. akorenny@princeton.edu
Annual Review of Cell and Developmental Biology
|October 13, 2012
Summary
The unfolded protein response (UPR) maintains endoplasmic reticulum (ER) function by sensing and responding to misfolded proteins. This critical cellular process, involving sensors like Ire1 and PERK, can shift from promoting survival to triggering apoptosis if homeostasis is not restored.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- The unfolded protein response (UPR) is a crucial cellular pathway that maintains endoplasmic reticulum (ER) homeostasis.
- It involves dedicated sensors that detect misfolded proteins within the ER lumen.
Purpose of the Study:
- To discuss the molecular understanding of the UPR.
- To focus on the structural biology of key UPR sensors in higher eukaryotes.
Main Methods:
- Review of emerging molecular data on UPR.
- Focus on structural biology of Ire1 and PERK sensors.
Main Results:
- The UPR activates transcriptional programs to increase ER capacity.
- In metazoans, UPR also regulates translation to reduce protein synthesis load.
- UPR can switch from a pro-survival to an apoptotic pathway if ER homeostasis is not achieved.
Conclusions:
- The UPR is a complex, coordinated gene response involving multiple sensors (Ire1, PERK, ATF6 in humans).
- Structural insights into Ire1 and PERK are advancing our understanding of UPR mechanisms.
Related Concept Videos
01:31Regulation of the Unfolded Protein Response
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...
01:37The Unfolded Protein Response
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...
01:34Directing Proteins to the Rough Endoplasmic Reticulum
The organelle-specific signaling sequences direct proteins synthesized in the cytosol to their final destination like ER, mitochondria, peroxisomes, etc. Some of the proteins directed to ER are then trafficked via vesicles to other organelles within the cell or the extracellular environment through the Golgi complex. For example, the rough ER synthesizes soluble proteins for transportation to the lysosomes or secretion out of the cell. It can also synthesize transmembrane proteins that can...
01:29Protein Folding Quality Check in the RER
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...
01:32Export of Misfolded Proteins out of the ER
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...
01:26Protein Modifications in the RER
Modification of secretory and transmembrane proteins entering the rough ER begins in the ER lumen. These modifications aid in protein folding and stabilize the acquired tertiary structure. Protein modifications in the rough ER co-occur at different stages of protein folding.
Broadly, these modifications can be categorized into four main categories — glycosylation, formation of disulfide bonds, assembly of protein subunits, and specific proteolytic cleavages like removal of signal sequences.
Broadly, these modifications can be categorized into four main categories — glycosylation, formation of disulfide bonds, assembly of protein subunits, and specific proteolytic cleavages like removal of signal sequences.