Chemical‐Synthesis‐Based Approach to Glycoprotein Functions in the Endoplasmic Reticulum

• Published in: Chemistry : a European journal 2020-12, Vol.26 (67), p.15461-15470
• Main Authors: Ito, Yukishige, Kajihara, Yasuhiro, Takeda, Yoichi
• Format: Article
• Language: English
• Subjects: Calnexin; Calreticulin; Chaperones; Chemical synthesis; Chemistry; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Folding; folding cycle; Glucosidase; Glucosyltransferase; Glucosyltransferases - chemistry; Glucosyltransferases - metabolism; Glycoproteins; Glycoproteins - chemistry; Glycoproteins - metabolism; high-mannose-type glycans; Lectins; Lectins - chemistry; Lectins - metabolism; Mannose; native chemical ligation; Polypeptides; Polysaccharides; Polysaccharides - chemistry; Polysaccharides - metabolism; Quality control; Signal quality; stereoselective synthesis; Substrates
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202004158

The introduction of Asn‐linked glycans to nascent polypeptides occurs in the lumen of the endoplasmic reticulum of eukaryotic cells. After the removal of specific sugar residues, glycoproteins acquire signals in the glycoprotein quality control (GPQC) system and enter the folding cycle composed of lectin‐chaperones calnexin (CNX) and calreticulin (CRT), glucosidase II (G‐II), and UDP‐Glc:glycoprotein glucosyltransferase (UGGT). G‐II initiates glycoproteins’ entry and exit from the cycle, and UGGT serves as the “folding sensor”. This account summarizes our effort to analyze the properties of enzymes and lectins that play important roles in GPQC, especially those involved in the CNX/CRT cycle. To commence our study, general methods for the synthesis of high‐mannose‐type glycans and glycoproteins were established. Based on these, various substrates to analyze components of the GPQC were created, and properties of CRT, G‐II, and UGGT have been clarified. High‐mannose‐type glycans are introduced to specific asparagine residues of nascent polypeptides in the endoplasmic reticulum (ER) of eukaryotic cells. They serve as key signals in the glycoprotein quality control (GPQC) system. To conduct precise analysis of GPQC, properly functionalized glycans and homogeneously glycosylated proteins were chemically synthesized and employed as substrates of components of GPQC. This Minireview highlights the strength of approaches based on chemical synthesis to understand biological events.