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Structural characterisation 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 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 cross-linking by simultaneous binding to sulfated and non-sulfated (but not sialylated) glycosphingolipids and glycoproteins; facilitating stabilisation 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 cross-linking by simultaneous binding to sulfated and non-sulfated (but not sialylated) glycosphingolipids and glycoproteins; facilitating stabilisation 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 recognise 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 characterisation 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. This article is protected by copyright. All rights reserved. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
The FEBS Journal
volume
282
issue
17
pages
3348 - 3367
publisher
Federation of European Neuroscience Societies and Blackwell Publishing Ltd
external identifiers
  • pmid:26077389
  • wos:000360629200009
  • scopus:84940722610
ISSN
1742-464X
DOI
10.1111/febs.13348
language
English
LU publication?
yes
id
15e575b3-9ca9-43a3-b457-3e3d6a33e77c (old id 7486018)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26077389?dopt=Abstract
date added to LUP
2015-07-08 16:40:42
date last changed
2017-08-13 03:05:02
@article{15e575b3-9ca9-43a3-b457-3e3d6a33e77c,
  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 cross-linking by simultaneous binding to sulfated and non-sulfated (but not sialylated) glycosphingolipids and glycoproteins; facilitating stabilisation 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 recognise 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 characterisation 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. This article is protected by copyright. All rights reserved.},
  author       = {Bum-Erdene, Khuchtumur and Leffler, Hakon and Nilsson, Ulf J and Blanchard, Helen},
  issn         = {1742-464X},
  language     = {eng},
  number       = {17},
  pages        = {3348--3367},
  publisher    = {Federation of European Neuroscience Societies and Blackwell Publishing Ltd},
  series       = {The FEBS Journal},
  title        = {Structural characterisation 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},
  volume       = {282},
  year         = {2015},
}