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Protein Folding Quality Check in the RER

Protein 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...

Calmodulin-dependent Signaling

Calmodulin-dependent Signaling

Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...

Role of ER in the Secretory Pathway

Role of ER in the Secretory Pathway

Eukaryotic cells have a special pathway that enables communication between various intracellular membrane-bound compartments and also with the extracellular environment. This pathway is termed as the secretory pathway.
Components of the secretory pathway
About a third of proteins synthesized in the cell are sorted via the secretory route. They shuffle between different compartments in membrane-bound vesicles until they reach their final destination. The main intracellular compartments involved...

ER Retrieval Pathway

ER Retrieval Pathway

In the secretory pathway, vesicles transport proteins from one cellular compartment to another in forward transport to deliver the protein to its correct location. Occasionally, misfolded proteins and incorrect proteins escape their original compartments, and a retrieval pathway is used to return the escaped proteins to their original compartment.
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Regulation of the Unfolded Protein Response

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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...

Export of Misfolded Proteins out of the ER

Export 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...

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Related Experiment Video

Updated: Jul 24, 2025

Live Cell Calcium Imaging Combined with siRNA Mediated Gene Silencing Identifies Ca2+ Leak Channels in the ER Membrane and their Regulatory Mechanisms

Live Cell Calcium Imaging Combined with siRNA Mediated Gene Silencing Identifies Ca2+ Leak Channels in the ER Membrane and their Regulatory Mechanisms

Published on: July 7, 2011

Calreticulin: Endoplasmic reticulum Ca²⁺ gatekeeper.

Marek Michalak¹

¹Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.

Journal of Cellular and Molecular Medicine

|July 10, 2023

Summary

Calreticulin, an endoplasmic reticulum (ER) protein, is crucial for managing calcium (Ca²⁺) levels and signaling. Its proper function is vital for cellular health and preventing diseases linked to calcium imbalance.

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Last Updated: Jul 24, 2025

Live Cell Calcium Imaging Combined with siRNA Mediated Gene Silencing Identifies Ca2+ Leak Channels in the ER Membrane and their Regulatory Mechanisms

Live Cell Calcium Imaging Combined with siRNA Mediated Gene Silencing Identifies Ca2+ Leak Channels in the ER Membrane and their Regulatory Mechanisms

Published on: July 7, 2011

Direct Imaging of ER Calcium with Targeted-Esterase Induced Dye Loading TED

Direct Imaging of ER Calcium with Targeted-Esterase Induced Dye Loading TED

Published on: May 7, 2013

Monitoring Endoplasmic Reticulum Calcium Homeostasis Using a Gaussia Luciferase SERCaMP

Monitoring Endoplasmic Reticulum Calcium Homeostasis Using a Gaussia Luciferase SERCaMP

Published on: September 6, 2015

Area of Science:

Cell Biology
Biochemistry
Molecular Medicine

Background:

Endoplasmic reticulum (ER) luminal calcium (Ca²⁺) is essential for cellular function and signaling.
Calreticulin is a key ER-resident protein involved in Ca²⁺ homeostasis and chaperone activity.

Purpose of the Study:

To elucidate the multifaceted roles of calreticulin in regulating ER luminal Ca²⁺.
To highlight calreticulin's function as an ER Ca²⁺ sensor and its impact on cellular processes.

Main Methods:

Review of established research on calreticulin's structure and function.
Analysis of calreticulin's interactions with Ca²⁺ handling molecules and substrates.
Examination of calreticulin's role in Ca²⁺-dependent cellular events.

Main Results:

Calreticulin critically maintains ER Ca²⁺ supply, access, and utilization under various physiological conditions.
It acts as an ER luminal Ca²⁺ sensor, managing Ca²⁺-dependent events and interactions within the ER.
Calreticulin influences cellular processes beyond the ER, impacting broader cellular pathophysiology.

Conclusions:

Calreticulin is indispensable for ER Ca²⁺ homeostasis and cellular signaling.
Dysregulation of ER Ca²⁺ handling by calreticulin is implicated in numerous pathologies, including heart failure, neurodegeneration, and metabolic diseases.