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    GH18 ENDO-β-N-ACETYLGLUCOSAMINIDASES USE DISTINCT MECHANISMS TO PROCESS HYBRID-TYPE N-LINKED GLYCANS

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    Author
    Trastoy, Beatriz
    Du, Jonathan J
    Li, Chao
    García-Alija, Mikel
    Klontz, Erik H
    Roberts, Blaine R
    Donahue, Thomas C
    Wang, Lai-Xi
    Sundberg, Eric J
    Guerin, Marcelo E
    Date
    2021-07-26
    Journal
    Journal of Biological Chemistry
    Publisher
    Elsevier Ltd.
    Type
    Article
    
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    See at
    https://doi.org/10.1016/j.jbc.2021.101011
    Abstract
    N-glycosylation is one of the most abundant post-translational modifications of proteins, essential for many physiological processes, including protein folding, protein stability, oligomerization and aggregation, and molecular recognition events. Defects in the N-glycosylation pathway cause diseases that are classified as congenital disorders of glycosylation. The ability to manipulate protein N-glycosylation is critical not only to our fundamental understanding of biology, but also for the development of new drugs for a wide range of human diseases. Chemoenzymatic synthesis using engineered endo-β-N-acetylglucosaminidases (ENGases) has been used extensively to modulate the chemistry of N-glycosylated proteins. However, defining the molecular mechanisms by which ENGases specifically recognize and process N-glycans remains a major challenge. Here we present the X-ray crystal structure of the ENGase EndoBT-3987 from Bacteroides thetaiotaomicron in complex with a hybrid type (Hy-type) glycan product. In combination with alanine scanning mutagenesis, molecular docking calculations and enzymatic activity measurements conducted on a chemically engineered monoclonal antibody substrate unveil two mechanisms for Hy-type recognition and processing by paradigmatic ENGases. Altogether, the experimental data provide pivotal insight into the molecular mechanism of substrate recognition and specificity for GH18 ENGases and further advance our understanding of chemoenzymatic synthesis and remodeling of homogeneous N-glycan glycoproteins.
    Rights/Terms
    Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
    Keyword
    antibody glycoengineering
    carbohydrate active enzymes
    endo-β-N-acetylglucosaminidases
    enzyme specificity
    glycoprotein bioengineering
    glycoside hydrolases
    gut microbiome
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/16288
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.jbc.2021.101011
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