title: Structural basis for distinct binding properties of the human galectins to Thomsen-Friedenreich antigen.
abstract: The Thomsen-Friedenreich (TF or T) antigen, Galβ1-3GalNAcα1-O-Ser/Thr, is the core 1 structure of O-linked mucin type glycans appearing in tumor-associated glycosylation. The TF antigen occurs in about 90% of human cancer cells and is a potential ligand for the human endogenous galectins. It has been reported that human galectin-1 (Gal-1) and galectin-3 (Gal-3) can perform their cancer-related functions via specifically recognizing TF antigen. However, the detailed binding properties have not been clarified and structurally characterized. In this work, first we identified the distinct TF-binding abilities of Gal-1 and Gal-3. The affinity to TF antigen for Gal-3 is two orders of magnitude higher than that for Gal-1. The structures of Gal-3 carbohydrate recognition domain (CRD) complexed with TF antigen and derivatives, TFN and GM1, were then determined. These structures show a unique Glu-water-Arg-water motif-based mode as previously observed in the mushroom galectin AAL. The observation demonstrates that this recognition mode is commonly adopted by TF-binding galectins, either as endogenous or exogenous ones. The detailed structural comparisons between Gal-1 and Gal-3 CRD and mutagenesis experiments reveal that a pentad residue motif ((51)AHGDA(55)) at the loop (g1-L4) connecting β-strands 4 and 5 of Gal-1 produces a serious steric hindrance for TF binding. This motif is the main structural basis for Gal-1 with the low affinity to TF antigen. These findings provide the intrinsic structural elements for regulating the TF-binding activity of Gal-1 in some special conditions and also show certain target and approach for mediating some tumor-related bioactivities of human galectins.
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, People's Republic of China.
authors.forename: Cheng-Feng
authors.initials: CF
authors.lastname: Bian
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Sun
authors.forename: De-Feng
authors.initials: DF
authors.lastname: Li
authors.forename: Da-Cheng
authors.initials: DC
authors.lastname: Wang
mesh_terms: D000595:Amino Acid Sequence; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000378:metabolism*; D002241:Carbohydrates / Q000737:chemistry*; D018360:Crystallography, X-Ray; D037483:Galectin 1 / Q000737:chemistry* / Q000378:metabolism*; D037502:Galectin 3 / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008956:Models, Chemical; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D020349:Surface Plasmon Resonance
chemical_list: D015295:Antigens, Tumor-Associated, Carbohydrate; D002241:Carbohydrates; D037483:Galectin 1; D037502:Galectin 3; C016467:Thomsen-Friedenreich antigen