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Definition: How are misfolded proteins identified and targeted for degradation?

Misfolded proteins are proteins that have not adopted their correct three-dimensional structure, rendering them non-functional or potentially harmful to the cell. To maintain cellular homeostasis, cells have evolved various mechanisms to identify and target misfolded proteins for degradation.

Chaperone-Mediated Protein Quality Control

Cells employ a network of molecular chaperones to assist in protein folding and prevent the accumulation of misfolded proteins. Chaperones recognize exposed hydrophobic regions on misfolded proteins and facilitate their refolding into their native conformation. If refolding is unsuccessful, chaperones can direct the misfolded proteins to degradation pathways.

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Ubiquitin-Proteasome System

The ubiquitin-proteasome system (UPS) is a major pathway for targeted protein degradation in eukaryotic cells. Misfolded proteins are recognized by specific E3 ubiquitin ligases, which catalyze the attachment of ubiquitin molecules to the misfolded protein. The addition of ubiquitin serves as a signal for the proteasome, a large protein complex, to recognize and degrade the tagged protein.

Endoplasmic Reticulum-Associated Degradation (ERAD)

The endoplasmic reticulum (ER) is responsible for the folding and quality control of membrane and secretory proteins. When misfolded proteins are detected in the ER, they are retrotranslocated back into the cytosol, where they can be targeted for degradation by the UPS. ERAD involves a series of coordinated steps, including recognition of misfolded proteins, extraction from the ER membrane, ubiquitination, and proteasomal degradation.

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Autophagy

Autophagy is a cellular process that involves the degradation of cellular components, including misfolded proteins, through the formation of double-membrane vesicles called autophagosomes. Misfolded proteins can be sequestered into autophagosomes and delivered to lysosomes for degradation. Autophagy serves as a quality control mechanism to remove damaged or unnecessary proteins and maintain cellular homeostasis.

Conclusion

The identification and targeted degradation of misfolded proteins are crucial for cellular health and function. Cells employ various mechanisms, such as chaperone-mediated protein quality control, the ubiquitin-proteasome system, endoplasmic reticulum-associated degradation, and autophagy, to ensure the proper folding and disposal of misfolded proteins. Understanding these processes is essential for developing therapeutic strategies to prevent the accumulation of misfolded proteins, which are associated with numerous diseases, including neurodegenerative disorders.

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Keywords: proteins, misfolded, degradation, protein, ubiquitin, cellular, targeted, quality, control