Protein Folding & N-Linked Glycosylation (Advanced)

N-linked glycosylation

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

14- sugar oligosaccharide

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

CLINICAL CORRELATIONS

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

Protein Folding & N-Linked Glycosylation (Advanced)

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