Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Structural characterization of human galectin-4 C-terminal domain : Elucidating the molecular basis for recognition of glycosphingolipids, sulfated saccharides and blood group antigens

Bum-Erdene, Khuchtumur ; Leffler, Hakon LU ; Nilsson, Ulf J. LU and Blanchard, Helen (2015) In The FEBS Journal 282(17). p.3348-3367
Abstract

Human galectin-4 is a lectin that is expressed mainly in the gastrointestinal tract and exhibits metastasis-promoting roles in some cancers. Its tandem-repeat nature exhibits two distinct carbohydrate recognition domains allowing crosslinking by simultaneous binding to sulfated and non-sulfated (but not sialylated) glycosphingolipids and glycoproteins, facilitating stabilization of lipid rafts. Critically, galectin-4 exerts favourable or unfavourable effects depending upon the cancer. Here we report the first X-ray crystallographic structural information on human galectin-4, specifically the C-terminal carbohydrate recognition domain of human (galectin-4C) in complex with lactose, lactose-3′-sulfate, 2′-fucosyllactose, lacto-N-tetraose... (More)

Human galectin-4 is a lectin that is expressed mainly in the gastrointestinal tract and exhibits metastasis-promoting roles in some cancers. Its tandem-repeat nature exhibits two distinct carbohydrate recognition domains allowing crosslinking by simultaneous binding to sulfated and non-sulfated (but not sialylated) glycosphingolipids and glycoproteins, facilitating stabilization of lipid rafts. Critically, galectin-4 exerts favourable or unfavourable effects depending upon the cancer. Here we report the first X-ray crystallographic structural information on human galectin-4, specifically the C-terminal carbohydrate recognition domain of human (galectin-4C) in complex with lactose, lactose-3′-sulfate, 2′-fucosyllactose, lacto-N-tetraose and lacto-N-neotetraose. These structures enable elucidation of galectin-4C binding fine-specificity towards sulfated and non-sulfated lacto- and neolacto-series sphingolipids as well as to human blood group antigens. Analysis of the lactose-3′-sulfate complex structure shows that galectin-4C does not recognize the sulfate group using any specific amino acid, but binds the ligand nonetheless. Complex structures with lacto-N-tetraose and lacto-N-neotetraose displayed differences in binding interactions exhibited by the non-reducing-end galactose. That of lacto-N-tetraose points outward from the protein surface whereas that of lacto-N-neotetraose interacts directly with the protein. Recognition patterns of human galectin-4C towards lacto- and neolacto-series glycosphingolipids are similar to those of human galectin-3; however, detailed scrutiny revealed differences stemming from the extended binding site that offer distinction in ligand profiles of these two galectins. Structural characterization of the complex with 2′-fucosyllactose, a carbohydrate with similarity to the H antigen, and molecular dynamics studies highlight structural features that allow specific recognition of A and B antigens, whilst a lack of interaction with the 2′-fucose of blood group antigens was revealed. Database accession codes 4YLZ, 4YM0, 4YM1, 4YM2, 4YM3. Human galectin-4 exerts favourable or unfavourable effects depending upon the particular cancer. Two distinct carbohydrate recognition domains enable cross-linking by simultaneous binding to ligands including glycosphingolipids and glycoproteins. Our elucidation of the first crystal structure of human galectin-4 C-terminal carbohydrate recognition domain-ligand complexes provides insight into galectin-4C binding fine-specificity towards lacto- and neolacto-series sphingolipids and to human blood group antigens.

(Less)
Please use this url to cite or link to this publication:
author
; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
blood group antigen, crystal structure, galectin-4, glycosphingolipid, oligosaccharide
in
The FEBS Journal
volume
282
issue
17
pages
20 pages
publisher
Wiley-Blackwell
external identifiers
  • pmid:26077389
  • wos:000360629200009
  • scopus:84940722610
  • pmid:26077389
ISSN
1742-464X
DOI
10.1111/febs.13348
language
English
LU publication?
yes
id
15e575b3-9ca9-43a3-b457-3e3d6a33e77c (old id 7486018)
date added to LUP
2016-04-01 09:59:58
date last changed
2023-02-08 07:48:13
@article{15e575b3-9ca9-43a3-b457-3e3d6a33e77c,
  abstract     = {{<p>Human galectin-4 is a lectin that is expressed mainly in the gastrointestinal tract and exhibits metastasis-promoting roles in some cancers. Its tandem-repeat nature exhibits two distinct carbohydrate recognition domains allowing crosslinking by simultaneous binding to sulfated and non-sulfated (but not sialylated) glycosphingolipids and glycoproteins, facilitating stabilization of lipid rafts. Critically, galectin-4 exerts favourable or unfavourable effects depending upon the cancer. Here we report the first X-ray crystallographic structural information on human galectin-4, specifically the C-terminal carbohydrate recognition domain of human (galectin-4C) in complex with lactose, lactose-3′-sulfate, 2′-fucosyllactose, lacto-N-tetraose and lacto-N-neotetraose. These structures enable elucidation of galectin-4C binding fine-specificity towards sulfated and non-sulfated lacto- and neolacto-series sphingolipids as well as to human blood group antigens. Analysis of the lactose-3′-sulfate complex structure shows that galectin-4C does not recognize the sulfate group using any specific amino acid, but binds the ligand nonetheless. Complex structures with lacto-N-tetraose and lacto-N-neotetraose displayed differences in binding interactions exhibited by the non-reducing-end galactose. That of lacto-N-tetraose points outward from the protein surface whereas that of lacto-N-neotetraose interacts directly with the protein. Recognition patterns of human galectin-4C towards lacto- and neolacto-series glycosphingolipids are similar to those of human galectin-3; however, detailed scrutiny revealed differences stemming from the extended binding site that offer distinction in ligand profiles of these two galectins. Structural characterization of the complex with 2′-fucosyllactose, a carbohydrate with similarity to the H antigen, and molecular dynamics studies highlight structural features that allow specific recognition of A and B antigens, whilst a lack of interaction with the 2′-fucose of blood group antigens was revealed. Database accession codes 4YLZ, 4YM0, 4YM1, 4YM2, 4YM3. Human galectin-4 exerts favourable or unfavourable effects depending upon the particular cancer. Two distinct carbohydrate recognition domains enable cross-linking by simultaneous binding to ligands including glycosphingolipids and glycoproteins. Our elucidation of the first crystal structure of human galectin-4 C-terminal carbohydrate recognition domain-ligand complexes provides insight into galectin-4C binding fine-specificity towards lacto- and neolacto-series sphingolipids and to human blood group antigens.</p>}},
  author       = {{Bum-Erdene, Khuchtumur and Leffler, Hakon and Nilsson, Ulf J. and Blanchard, Helen}},
  issn         = {{1742-464X}},
  keywords     = {{blood group antigen; crystal structure; galectin-4; glycosphingolipid; oligosaccharide}},
  language     = {{eng}},
  number       = {{17}},
  pages        = {{3348--3367}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{The FEBS Journal}},
  title        = {{Structural characterization of human galectin-4 C-terminal domain : Elucidating the molecular basis for recognition of glycosphingolipids, sulfated saccharides and blood group antigens}},
  url          = {{http://dx.doi.org/10.1111/febs.13348}},
  doi          = {{10.1111/febs.13348}},
  volume       = {{282}},
  year         = {{2015}},
}