Martin, Joanne C. and Fadda, Elisa and Keigo, Ito and Woods, Robert J.
(2014)
Defining the structural origin of the substrate sequence
independence of O-GlcNAcase using a combination
of molecular docking and dynamics simulation.
Glycobiology, 24 (1).
pp. 85-96.
ISSN 0959-6658
Abstract
Protein glycosylation with O-linked N-acetylglucosamine
(O-GlcNAc) is a post-translational modification of serine/
threonine residues in nucleocytoplasmic proteins. O-GlcNAc
has been shown to play a role in many different cellular
processes and O-GlcNAcylation is often found at sites that
are also known to be phosphorylated. Unlike phosphorylation,
O-GlcNAc levels are regulated by only two enzymes,
O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase
(O-GlcNAcase or OGA). So far, no obvious consensus
sequence has been found for sites of O-GlcNAcylation.
Additionally, O-GlcNAcase recognizes and cleaves all
O-GlcNAcylated proteins, independent of their sequence.
In this work, we generate and analyze five models of
O-GlcNAcylated peptides in complex with a bacterial OGA.
Each of the five glycopeptides bind to OGA in a similar
fashion, with OGA–peptide interactions primarily, but not exclusively,
involving the peptide backbone atoms, thus explaining
the lack of sensitivity to peptide sequence. Nonetheless,
differences in peptide sequences, particularly at the −1 to −4
positions, lead to variations in predicted affinity, consistent
with observed experimental variations in enzyme kinetics.
The potential exists, therefore, to employ the present analysis
to guide the development glycopeptide-specific inhibitors, or
conversely, the conversion of OGA into a reagent that could
target specific O-GlcNAcylated peptide sequences.
| Item Type: |
Article
|
| Additional Information: |
© The Author 2013. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/
3.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use,
please contact journals.permissions@oup.com |
| Keywords: |
β-N-Acetylglucosaminidase
(O-GlcNAcase); GLYCAM; Molecular dynamics; O-Linked
N-acetyl-glucosamine (O-GlcNAc); Protein glycosylation; |
| Academic Unit: |
Faculty of Science and Engineering > Chemistry |
| Item ID: |
6991 |
| Identification Number: |
https://doi.org/10.1093/glycob/cwt094 |
| Depositing User: |
Elisa Fadda
|
| Date Deposited: |
26 Feb 2016 15:02 |
| Journal or Publication Title: |
Glycobiology |
| Publisher: |
Oxford University Press |
| Refereed: |
Yes |
| URI: |
|
| Use Licence: |
This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available
here |
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