Notch-modifying xylosyltransferase structures support an SNi-like retaining mechanism
Abstract
A major question remaining in glycobiology is how a glycosyltransferase (GT) that retains the anomeric linkage of a sugar catalyzes the reaction. Xyloside α-1,3-xylosyltransferase (XXYLT1) is a retaining GT that regulates Notch receptor activation by adding xylose to the Notch extracellular domain. Here, using natural acceptor and donor substrates and active Mus musculus XXYLT1, we report a series of crystallographic snapshots along the reaction, including an unprecedented natural and competent Michaelis reaction complex for retaining enzymes. These structures strongly support the SNi-like reaction as the retaining mechanism for XXYLT1. Unexpectedly, the epidermal growth factor–like repeat acceptor substrate undergoes a large conformational change upon binding to the active site, providing a structural basis for substrate specificity. As a result, our improved understanding of this retaining enzyme will accelerate the design of retaining GT inhibitors that can modulate Notch activity in pathological situations in which Notch dysregulation is known to cause cancer or developmental disorders.
- Authors:
-
- Brookhaven National Lab. (BNL), Upton, NY (United States)
- Brookhaven National Lab. (BNL), Upton, NY (United States); Stony Brook Univ., Stony Brook, NY (United States)
- Stony Brook Univ., Stony Brook, NY (United States)
- Hannover Medical School, Hannover (Germany)
- Publication Date:
- Research Org.:
- Brookhaven National Laboratory (BNL), Upton, NY (United States)
- Sponsoring Org.:
- National Institute of Health
- OSTI Identifier:
- 1234375
- Report Number(s):
- BNL-111663-2015-JA
Journal ID: ISSN 1552-4450
- Grant/Contract Number:
- SC00112704
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Chemical Biology
- Additional Journal Information:
- Journal Volume: 11; Journal Issue: 11; Journal ID: ISSN 1552-4450
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; cancer; carbohydrates; enzyme mechanisms; X-ray crystallography
Citation Formats
Yu, Hongjun, Li, Huilin, Takeuchi, Megumi, LeBarron, Jamie, Kantharia, Joshua, London, Erwin, Bakker, Hans, Haltiwanger, Robert S., and Takeuchi, Hideyuki. Notch-modifying xylosyltransferase structures support an SNi-like retaining mechanism. United States: N. p., 2015.
Web. doi:10.1038/nchembio.1927.
Yu, Hongjun, Li, Huilin, Takeuchi, Megumi, LeBarron, Jamie, Kantharia, Joshua, London, Erwin, Bakker, Hans, Haltiwanger, Robert S., & Takeuchi, Hideyuki. Notch-modifying xylosyltransferase structures support an SNi-like retaining mechanism. United States. https://doi.org/10.1038/nchembio.1927
Yu, Hongjun, Li, Huilin, Takeuchi, Megumi, LeBarron, Jamie, Kantharia, Joshua, London, Erwin, Bakker, Hans, Haltiwanger, Robert S., and Takeuchi, Hideyuki. Mon .
"Notch-modifying xylosyltransferase structures support an SNi-like retaining mechanism". United States. https://doi.org/10.1038/nchembio.1927. https://www.osti.gov/servlets/purl/1234375.
@article{osti_1234375,
title = {Notch-modifying xylosyltransferase structures support an SNi-like retaining mechanism},
author = {Yu, Hongjun and Li, Huilin and Takeuchi, Megumi and LeBarron, Jamie and Kantharia, Joshua and London, Erwin and Bakker, Hans and Haltiwanger, Robert S. and Takeuchi, Hideyuki},
abstractNote = {A major question remaining in glycobiology is how a glycosyltransferase (GT) that retains the anomeric linkage of a sugar catalyzes the reaction. Xyloside α-1,3-xylosyltransferase (XXYLT1) is a retaining GT that regulates Notch receptor activation by adding xylose to the Notch extracellular domain. Here, using natural acceptor and donor substrates and active Mus musculus XXYLT1, we report a series of crystallographic snapshots along the reaction, including an unprecedented natural and competent Michaelis reaction complex for retaining enzymes. These structures strongly support the SNi-like reaction as the retaining mechanism for XXYLT1. Unexpectedly, the epidermal growth factor–like repeat acceptor substrate undergoes a large conformational change upon binding to the active site, providing a structural basis for substrate specificity. As a result, our improved understanding of this retaining enzyme will accelerate the design of retaining GT inhibitors that can modulate Notch activity in pathological situations in which Notch dysregulation is known to cause cancer or developmental disorders.},
doi = {10.1038/nchembio.1927},
journal = {Nature Chemical Biology},
number = 11,
volume = 11,
place = {United States},
year = {Mon Sep 28 00:00:00 EDT 2015},
month = {Mon Sep 28 00:00:00 EDT 2015}
}
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