Structural basis for the initiation of glycosaminoglycan biosynthesis by human xylosyltransferase 1
File(s)
Published version
Author(s)
Briggs, David
Hohenester, E
Type
Journal Article
Abstract
Proteoglycans (PGs) are essential components of the animal extracellular matrix and required for
cell adhesion, migration, signalling, and immune function. PGs are composed of a core protein and
long glycosaminoglycan (GAG) chains, which often specify PG function. GAG biosynthesis is
initiated by peptide O-xylosyltransferases, which transfer xylose onto selected serine residues in the
core proteins. We have determined crystal structures of human xylosyltransferase 1 (XT1) in
complex with the sugar donor, UDP-xylose, and various acceptor peptides. The structures reveal
unique active site features that, in conjunction with functional experiments, explain the substrate
specificity of XT1. A constriction within the peptide-binding cleft requires the acceptor serine to be
followed by glycine or alanine. The remainder of the cleft can accommodate a wide variety of
sequences, but with a general preference for acidic residues. These findings provide a framework
for understanding the selectivity of GAG attachment.
cell adhesion, migration, signalling, and immune function. PGs are composed of a core protein and
long glycosaminoglycan (GAG) chains, which often specify PG function. GAG biosynthesis is
initiated by peptide O-xylosyltransferases, which transfer xylose onto selected serine residues in the
core proteins. We have determined crystal structures of human xylosyltransferase 1 (XT1) in
complex with the sugar donor, UDP-xylose, and various acceptor peptides. The structures reveal
unique active site features that, in conjunction with functional experiments, explain the substrate
specificity of XT1. A constriction within the peptide-binding cleft requires the acceptor serine to be
followed by glycine or alanine. The remainder of the cleft can accommodate a wide variety of
sequences, but with a general preference for acidic residues. These findings provide a framework
for understanding the selectivity of GAG attachment.
Date Issued
2018-06-05
Date Acceptance
2018-03-20
Citation
Structure, 2018, 26 (6), pp.801-809.e3
ISSN
0969-2126
Publisher
Elsevier
Start Page
801
End Page
809.e3
Journal / Book Title
Structure
Volume
26
Issue
6
Copyright Statement
© 2018 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Sponsor
Biotechnology and Biological Sciences Research Council (BBSRC)
Imperial College Trust
Wellcome Trust
Grant Number
BB/D524840/1
P48895
202926/Z/16/Z
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Biophysics
Cell Biology
O-GLCNAC TRANSFERASE
PROTEIN LINKAGE REGION
CRYSTAL-STRUCTURE
FUNCTIONAL-CHARACTERIZATION
XT-II
ENZYME
XYLOSE
XYLT1
PROTEOGLYCANS
MUTATIONS
X-ray crystallography
enzyme catalysis
glycosyltransferase
proteoglycan
06 Biological Sciences
08 Information And Computing Sciences
03 Chemical Sciences
Publication Status
Published
Date Publish Online
2018-04-19