Protein Folding & N-Linked Glycosylation (Advanced)
- Transfer of 14-sugar oligosaccharide onto side chain amide of Asn residue.
- Is an ER event
- Occurs co-translationally
- Occurs on Asn-X-Ser/Thr sequence
- Synthesized on dolichol (lipid carrier) for N-linked glycosylation
- 2 N-acetylglucosamine sugars
- 9 mannose residues
- 3 glucose residues
Events of N-glycosylation
1. Nascent protein imports co-translationally through translocon
2. Oligosaccharyl transferase transfers oligossacharide from dolichol to N-amide of Asn residue
3. 2 glucose residues trimmed as protein is released from translocon
4. Calreticulin helps protein fold
- Last glucose trimmed --> calreticulin releases protein
- Quality control by glucosyltransferase
chaperones (e.g calreticulin)
- Help the protein fold along most energetically favorable pathway
- Make folding process more efficient and reliable
- Release protein when process is complete
Glucosyltransferase
- Involved in glycoprotein folding quality control
- Detects no exposed hydrophobic regions: releases protein
- Detects some exposed hydrophobic regions: adds glucose residue to oligosaccharide chain --> glycoprotein returns to calreticulin and refolds
- Detects many exposed hydrophobic regions: protein cannot be folded correctly --> loses mannose residues--> targeted to cytosol for degradation
Over 35 diseases
• Directly or indirectly related to improper protein folding.
Cystic fibrosis
• Genetic disorder
• Slightly misfolded protein prematurely degraded by ER quality control process