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

• DOI: 10.1016/j.molcel.2023.11.006
• Publication Date: 2023-12-04T15:34:11Z
• Authors: Kevin P. Guay; Haiping Ke; Nathan P. Canniff; Gracie T. George; Stephen J. Eyles; Malaiyalam Mariappan; Joseph N. Contessa; Anne Gershenson; Lila M. Gierasch; Daniel N. Hebert
• Keywords: Quality Control; Protein Folding; Polysaccharides; Lectins; Humans; Molecular Chaperones

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.