Structural insights into the recognition mechanism between an antitumor galectin AAL and the Thomsen-Friedenreich antigen.
Thomsen-Friedenreich (TF) antigen, which plays an important role in the regulation of cancer cell proliferation, occurs in ∼90% of all human cancers and precancerous conditions. Although TF antigen has been known for almost 80 yr as a pancarcinoma antigen, the recognition mechanism between TF antigen and target protein has not been structurally characterized. A number of studies indicated that TF disaccharide is a potential ligand of the galactoside-binding galectins. In this work, we identified the TF antigen as a potential ligand of the antitumor galectin AAL (Agrocybe aegerita lectin) through glycan array analysis and reported the crystal structure of AAL complexed with the TF antigen. The structure provides a first look at the recognition mode between AAL and TF antigen, which is unique in a conservative (Glu-water-Arg-water) structural motif-based hydrogen bond network. Structure-based mutagenesis analysis further revealed the residues responsible for recognition specificity and binding affinity. Crystal structures of AAL complexed with two other TF-containing glycans showed that the unique TF recognition mode is kept intact, which may be commonly adopted in some cancer-related galectins. The finding provided the new target and approach for the antitumor drug design and relative strategy based on the AAL-TF recognition mode as a prototype model.
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, PR China.
Lei
L
Feng
Hui
H
Sun
Ying
Y
Zhang
De-Feng
DF
Li
Da-Cheng
DC
Wang
D015295:Antigens, Tumor-Associated, Carbohydrate / Q000737:chemistry / Q000276:immunology*; D017209:Apoptosis; D002151:Calorimetry / Q000379:methods; D037161:Galectins / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D006860:Hydrogen Bonding; D011487:Protein Conformation
D015295:Antigens, Tumor-Associated, Carbohydrate; D037161:Galectins; C016467:Thomsen-Friedenreich antigen