Structural Basis for the Initiation of Glycosaminoglycan Biosynthesis by Human Xylosyltransferase 1

Structure. 2018 Jun 5;26(6):801-809.e3. doi: 10.1016/j.str.2018.03.014. Epub 2018 Apr 19.

Abstract

Proteoglycans (PGs) are essential components of the animal extracellular matrix and are required for cell adhesion, migration, signaling, 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.

Keywords: X-ray crystallography; enzyme catalysis; glycosyltransferase; proteoglycan.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Crystallography, X-Ray
  • Glycosaminoglycans / biosynthesis*
  • Glycosylation
  • Humans
  • Models, Molecular
  • Pentosyltransferases / chemistry*
  • Pentosyltransferases / metabolism*
  • Protein Binding
  • Protein Conformation
  • Serine / chemistry
  • Substrate Specificity
  • Uridine Diphosphate Xylose / metabolism*

Substances

  • Glycosaminoglycans
  • Uridine Diphosphate Xylose
  • Serine
  • Pentosyltransferases
  • UDP xylose-protein xylosyltransferase