mannose trimming involved in glycoprotein ERAD pathway

Definition

Target type: biologicalprocess

The removal of one or more alpha 1,2-linked mannose residues from a mannosylated protein that occurs as part of glycoprotein ER-associated glycoprotein degradation (gpERAD). [GO_REF:0000060, GOC:bf, GOC:PARL, GOC:TermGenie, PMID:24519966]

Mannose trimming is a crucial step in the endoplasmic reticulum-associated protein degradation (ERAD) pathway, a quality control mechanism that ensures proper folding and assembly of proteins within the endoplasmic reticulum (ER). Misfolded or unassembled proteins accumulate in the ER lumen and are targeted for degradation by the ERAD machinery. Mannose trimming plays a key role in this process by providing a signal for recognition and extraction of these misfolded proteins.

The ERAD pathway involves several distinct steps, including recognition of misfolded proteins, their retrotranslocation from the ER lumen into the cytosol, and subsequent degradation by the proteasome. Mannose trimming is a crucial event in the early stages of this pathway, specifically in the recognition step.

**The role of mannose trimming in ERAD:**

1. **Initial glycosylation:** Newly synthesized proteins in the ER lumen undergo N-linked glycosylation, where oligosaccharide chains are attached to asparagine residues. These oligosaccharides typically contain multiple mannose residues, forming a complex sugar structure.

2. **Mannose trimming by glucosidases:** In the ER, a series of glucosidases (enzymes that cleave glucose residues) remove glucose molecules from the N-linked glycans. This process is crucial for quality control, as it allows the ER to monitor the proper folding and assembly of newly synthesized proteins.

3. **Mannose trimming by mannosidases:** If the protein is properly folded and assembled, it will be released from the ER and proceed to its final destination. However, if a protein fails to fold correctly, it will be recognized by the ERAD machinery. A key step in this recognition process is the removal of mannose residues from the N-linked glycans.

4. **Signal for ERAD:** The removal of mannose residues by mannosidases exposes a specific signal for the ERAD pathway. This signal is recognized by lectins, proteins that bind to specific carbohydrate structures. In the ER, lectins such as calnexin and calreticulin act as chaperones and help in the folding of newly synthesized proteins. However, if a protein fails to fold properly, it will be recognized by these lectins, and the removal of mannose residues triggers a switch in their interaction.

5. **Extraction and degradation:** Once recognized by the ERAD machinery, the misfolded protein is extracted from the ER lumen through a protein channel called the Sec61 translocon. This process, known as retrotranslocation, requires the activity of ATPase proteins that provide the energy for protein unfolding and translocation. The extracted protein is then ubiquitinated, a process where ubiquitin proteins are attached to the misfolded protein, targeting it for degradation by the proteasome.

**In summary, mannose trimming plays a critical role in the ERAD pathway by providing a signal for the recognition of misfolded proteins. The removal of mannose residues by mannosidases exposes a specific carbohydrate motif that is recognized by lectins, triggering a switch in their interaction with the protein. This leads to the recruitment of the ERAD machinery, extraction of the misfolded protein from the ER lumen, and its subsequent degradation by the proteasome.**'
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