Structural characterization of human galectin-4 C-terminal domain : Elucidating the molecular basis for recognition of glycosphingolipids, sulfated saccharides and blood group antigens
(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)
- author
- Bum-Erdene, Khuchtumur ; Leffler, Hakon LU ; Nilsson, Ulf J. LU and Blanchard, Helen
- organization
- publishing date
- 2015
- 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}},
}