A Novel Mechanism for Binding of Galactose-terminated Glycans by the C-type Carbohydrate Recognition Domain in Blood Dendritic Cell Antigen 2

J Biol Chem. 2015 Jul 3;290(27):16759-71. doi: 10.1074/jbc.M115.660613. Epub 2015 May 20.

Abstract

Blood dendritic cell antigen 2 (BDCA-2; also designated CLEC4C or CD303) is uniquely expressed on plasmacytoid dendritic cells. Stimulation of BDCA-2 with antibodies leads to an anti-inflammatory response in these cells, but the natural ligands for the receptor are not known. The C-type carbohydrate recognition domain in the extracellular portion of BDCA-2 contains a signature motif typical of C-type animal lectins that bind mannose, glucose, or GlcNAc, yet it has been reported that BDCA-2 binds selectively to galactose-terminated, biantennary N-linked glycans. A combination of glycan array analysis and binding competition studies with monosaccharides and natural and synthetic oligosaccharides have been used to define the binding epitope for BDCA-2 as the trisaccharide Galβ1-3/4GlcNAcβ1-2Man. X-ray crystallography and mutagenesis studies show that mannose is ligated to the conserved Ca(2+) in the primary binding site that is characteristic of C-type carbohydrate recognition domains, and the GlcNAc and galactose residues make additional interactions in a wide, shallow groove adjacent to the primary binding site. As predicted from these studies, BDCA-2 binds to IgG, which bears galactose-terminated glycans that are not commonly found attached to other serum glycoproteins. Thus, BDCA-2 has the potential to serve as a previously unrecognized immunoglobulin Fc receptor.

Keywords: CD303; CLEC4C; carbohydrate-binding protein; crystal structure; glycobiology; glycoprotein; lectin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Binding Sites
  • Carbohydrate Sequence
  • Crystallography, X-Ray
  • Galactose / metabolism*
  • Humans
  • Lectins, C-Type / chemistry*
  • Lectins, C-Type / genetics
  • Lectins, C-Type / metabolism*
  • Membrane Glycoproteins / chemistry*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Molecular Sequence Data
  • Polysaccharides / chemistry
  • Polysaccharides / metabolism*
  • Receptors, Immunologic / chemistry*
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*

Substances

  • CLEC4C protein, human
  • Lectins, C-Type
  • Membrane Glycoproteins
  • Polysaccharides
  • Receptors, Immunologic
  • Galactose

Associated data

  • PDB/1HZH
  • PDB/1SLA
  • PDB/3VYK
  • PDB/4KZV
  • PDB/4ZES
  • PDB/4ZET
  • PDB/4ZRV