ER chaperones use a protein folding and quality control glyco-code

N-glycans act as quality control tags by recruiting lectin chaperones to assist protein maturation in the endoplasmic reticulum. The location and composition of N-glycans (glyco-code) are key to the chaperone-selection process. Serpins, a class of serine protease inhibitors, fold non-sequentially to...

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Bibliographic Details
Published in:Molecular cell 2023-12, Vol.83 (24), p.4524-4537.e5
Main Authors: Guay, Kevin P, Ke, Haiping, Canniff, Nathan P, George, Gracie T, Eyles, Stephen J, Mariappan, Malaiyalam, Contessa, Joseph N, Gershenson, Anne, Gierasch, Lila M, Hebert, Daniel N
Format: Article
Language:English
Subjects:
Humans
Lectins - metabolism
Molecular Chaperones - metabolism
Polysaccharides - chemistry
Protein Folding
Quality Control
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Summary:N-glycans act as quality control tags by recruiting lectin chaperones to assist protein maturation in the endoplasmic reticulum. The location and composition of N-glycans (glyco-code) are key to the chaperone-selection process. Serpins, a class of serine protease inhibitors, fold non-sequentially to achieve metastable active states. Here, the role of the glyco-code in assuring successful maturation and quality control of two human serpins, alpha-1 antitrypsin (AAT) and antithrombin III (ATIII), is described. We find that AAT, which has glycans near its N terminus, is assisted by early lectin chaperone binding. In contrast, ATIII, which has more C-terminal glycans, is initially helped by BiP and then later by lectin chaperones mediated by UGGT reglucosylation. UGGT action is increased for misfolding-prone disease variants, and these clients are preferentially glucosylated on their most C-terminal glycan. Our study illustrates how serpins utilize N-glycan presence, position, and composition to direct their proper folding, quality control, and trafficking.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2023.11.006