Biochemistry · Topic
Glycoproteins and protein glycosylation (N- and O-linked) !
Many proteins get sugar chains attached in the ER and Golgi. The sugars help folding, sorting, stability, cell recognition and blood groups.
Updated 2026-11-01
Key facts
- N-linked: the sugar chain is attached to the amide N of asparagine in the sequence Asn-X-Ser/Thr (X ≠ proline), in the rough ER, during translation.
- N-glycans start as a 14-sugar block (Glc₃Man₉GlcNAc₂) built on dolichol phosphate and moved whole to the protein by oligosaccharyltransferase (OST); it is then trimmed in the ER and Golgi.
- O-linked: sugars are added one by one to the OH of serine or threonine (or hydroxylysine in collagen) in the Golgi; mucins and proteoglycans are O-glycosylated.
- Functions: folding quality control (calnexin/calreticulin), lysosomal targeting (mannose 6-phosphate), half-life in plasma, receptors and cell adhesion (selectins), ABO blood groups.
- Tunicamycin blocks the first step of the dolichol pathway; defects in the pathway cause congenital disorders of glycosylation (CDG).
In detail
- 1. On the cytosolic face of the ER, sugars are added to dolichol phosphate from nucleotide sugars (UDP-GlcNAc, GDP-mannose); the lipid then flips into the ER lumen and receives more mannose and glucose.
- 2. OST transfers the whole oligosaccharide to asparagine of the growing chain as it enters the ER.
- 3. Glucosidases I and II remove glucose; calnexin and calreticulin hold proteins with one glucose until they fold correctly (folding checkpoint). Misfolded proteins are sent to ER-associated degradation.
- 4. In the Golgi, mannose trimming and addition of GlcNAc, galactose, fucose and sialic acid create 'complex' glycans; some keep 'high-mannose' glycans.
- 5. Lysosomal enzymes receive mannose 6-phosphate in the cis-Golgi, the signal that sends them to lysosomes.
- 6. Glycation is different: a non-enzymatic attachment of glucose to proteins (for example HbA1c and advanced glycation end-products in diabetes).
Memory aid
N for asparagiNe (in the ER, en bloc); O for serine/thrEOnine OH (in the Golgi, one by one).
- Also called
- N-glycosylation, O-glycosylation, Dolichol pathway, Glycoproteins
Clinical notes
- Congenital disorders of glycosylation (for example PMM2-CDG) cause multisystem disease; transferrin isoelectric focusing is the screening test.
- I-cell disease is a defect of mannose 6-phosphate tagging: lysosomal enzymes are secreted into blood instead of reaching lysosomes.
- Sialylated mucins and altered glycans are tumour markers (CA-125, CA 19-9 recognise carbohydrate-rich epitopes).
Related conditions
- Congenital disorder of glycosylation type Ia (PMM2-CDG)
- I-cell disease (mucolipidosis II)
- Hurler syndrome (mucopolysaccharidosis type I)
Related
- Protein targeting and signal sequences
- Molecular chaperones and heat shock proteins
- Mannose 6-phosphate tagging (sending enzymes to the lysosome)
- Glycosaminoglycans (mucopolysaccharides)
- Cell organelles and their metabolism
- Collagen synthesis
- Immunoglobulins (antibodies)
- Carbohydrate chemistry
- Translation and the genetic code
Test yourself
Think of the answer, then tap the question to see it.
To which amino acid is an N-linked glycan attached, and in which sequence?
To asparagine, in the sequon Asn-X-Ser/Thr where X is any amino acid except proline.
What lipid carries the oligosaccharide before it is transferred to the protein?
Dolichol phosphate (dolichol pyrophosphate–oligosaccharide), in the ER membrane.
Where and how does O-glycosylation take place?
Mainly in the Golgi, adding sugars one at a time to the hydroxyl of serine or threonine.
What role do calnexin and calreticulin play?
They are lectin chaperones that hold monoglucosylated glycoproteins in the ER until they fold correctly.
Which test screens for congenital disorders of glycosylation?
Isoelectric focusing of serum transferrin, which shows the loss of sialic acid-containing glycans.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: PDB-101: Molecule of the Month: Oligosaccharyltransferase (RCSB Protein Data Bank (PDB-101), 2026); STT3A: Dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit STT3A (human) (UniProt, 2026); PMM2-congenital disorder of glycosylation: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).
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Representative model, for educational purposes only.