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

In English

Författare

Summary, in English

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.

Publiceringsår

2015

Språk

Engelska

Sidor

3348-3367

Publikation/Tidskrift/Serie

The FEBS Journal

Volym

282

Issue

17

Dokumenttyp

Artikel i tidskrift

Förlag

Wiley-Blackwell

Ämne

  • Other Basic Medicine

Nyckelord

  • blood group antigen
  • crystal structure
  • galectin-4
  • glycosphingolipid
  • oligosaccharide

Status

Published

ISBN/ISSN/Övrigt

  • ISSN: 1742-464X