regulation of protein folding in endoplasmic reticulum

Definition

Target type: biologicalprocess

Any process that modulates the rate, frequency or extent of the protein folding process that takes place in the endoplasmic reticulum (ER). Secreted, plasma membrane and organelle proteins are folded in the ER, assisted by chaperones and foldases (protein disulphide isomerases), and additional factors required for optimal folding (ATP, Ca2+ and an oxidizing environment to allow disulfide bond formation). [GOC:dph, GOC:tb]

Protein folding in the endoplasmic reticulum (ER) is a tightly regulated process essential for the production of functional proteins. The ER is a network of membrane-bound sacs and tubules within eukaryotic cells that serves as the site for protein synthesis, modification, and folding. Newly synthesized proteins enter the ER lumen through a protein translocation channel, where they encounter a complex machinery responsible for their proper folding.

The ER lumen contains a specialized set of molecular chaperones and folding enzymes that assist in the folding process. These chaperones, such as BiP (binding immunoglobulin protein), calnexin, and calreticulin, bind to unfolded or misfolded proteins, preventing aggregation and providing time for correct folding. BiP, a heat shock protein, is a key chaperone that binds to unfolded polypeptide chains, promoting their folding and preventing aggregation. Calnexin and calreticulin are lectin chaperones that recognize and bind to glycoproteins, facilitating their proper folding.

In addition to chaperones, the ER lumen also contains enzymes that catalyze specific modifications, such as disulfide bond formation and glycosylation, which contribute to protein folding and stability. Disulfide bonds are covalent linkages between cysteine residues that stabilize protein structure. Glycosylation, the addition of sugar molecules, can also promote proper folding and facilitate protein trafficking.

Quality control mechanisms ensure that only properly folded proteins exit the ER. Misfolded or unfolded proteins are recognized by ER-associated degradation (ERAD) pathways, which target them for ubiquitination and degradation by proteasomes. ERAD involves the recruitment of chaperones, ubiquitin ligases, and proteasome components to the ER membrane, leading to the retrotranslocation of misfolded proteins into the cytosol for degradation.

The unfolded protein response (UPR) is a signaling pathway that is activated when the ER experiences an accumulation of unfolded or misfolded proteins. The UPR aims to restore ER homeostasis by increasing the capacity for protein folding, reducing protein translation, and enhancing ERAD. Three transmembrane sensor proteins, IRE1, PERK, and ATF6, are activated by ER stress and trigger downstream signaling cascades.

IRE1 activates the splicing of XBP1 mRNA, leading to the production of a transcription factor that enhances the expression of chaperones and ERAD components. PERK phosphorylates eIF2α, a translation initiation factor, leading to a global reduction in protein synthesis. ATF6 translocates to the Golgi apparatus, where it is cleaved to release a transcription factor that upregulates the expression of genes involved in protein folding and ERAD.

The regulation of protein folding in the ER is a complex and dynamic process that involves multiple molecular chaperones, folding enzymes, quality control mechanisms, and signaling pathways. The proper folding of proteins is essential for their biological function and cell survival. Disruptions in ER protein folding can lead to various diseases, including cancer, neurodegenerative disorders, and metabolic diseases.'
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Proteins (1)

Compounds (10)