ERAD substrates: which way out?

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Protein folding begins as polypeptides emerge from the Sec61 translocon in the endoplasmic reticulum (ER).
• Nascent proteins require time to attain their native structure, with folding duration varying by gene product.
• Non-native folding intermediates must be shielded from molecular chaperones to prevent premature targeting to degradation pathways.

Purpose of the Study:

• To review recent advances in understanding the mechanisms of protein quality control within the ER.
• To elucidate how terminally misfolded polypeptides are identified and processed for degradation.
• To describe the extraction of misfolded proteins from the ER folding environment and their targeting to dislocons.

Main Methods:

• This review synthesizes findings from recent studies on protein folding and degradation in the ER.
• It focuses on the cellular machinery involved in recognizing and extracting misfolded proteins.
• The review examines the role of dislocons in the ER membrane for protein transfer.

Main Results:

• Terminally misfolded polypeptides are actively extracted from the ER lumen.
• Specific dislocon complexes in the ER membrane mediate the transfer of these proteins.
• This process facilitates the transfer of misfolded proteins to the cytoplasm for proteasomal degradation.

Conclusions:

• The ER employs sophisticated mechanisms to manage protein folding and quality control.
• Efficient extraction and degradation of terminally misfolded proteins are crucial to prevent cellular dysfunction.
• ER-associated degradation (ERAD) is a key pathway for maintaining proteostasis within the ER.