Delineating binding modes of Gal/GalNAc and structural elements of the molecular recognition of tumor-associated mucin glycopeptides by the human macrophage galactose-type lectin. 2014

Filipa Marcelo, and Fayna Garcia-Martin, and Takahiko Matsushita, and João Sardinha, and Helena Coelho, and Anneloes Oude-Vrielink, and Christiane Koller, and Sabine André, and Eurico J Cabrita, and Hans-Joachim Gabius, and Shin-Ichiro Nishimura, and Jesús Jiménez-Barbero, and F Javier Cañada
REQUIMTE, CQFB, Departamento de Química, Faculdade de Ciências e Tecnologia, UNL, 2829-516 Caparica (Portugal); Centro de Investigaciones Biológicas, CIB-CSIC, Ramiro de Maeztu 9, 28040 Madrid (Spain). filipa.marcelo@fct.unl.pt.

The human macrophage galactose-type lectin (MGL) is a key physiological receptor for the carcinoma-associated Tn antigen (GalNAc-α-1-O-Ser/Thr) in mucins. NMR and modeling-based data on the molecular recognition features of synthetic Tn-bearing glycopeptides by MGL are presented. Cognate epitopes on the sugar and matching key amino acids involved in the interaction were identified by saturation transfer difference (STD) NMR spectroscopy. Only the amino acids close to the glycosylation site in the peptides are involved in lectin contact. Moreover, control experiments with non-glycosylated MUC1 peptides unequivocally showed that the sugar residue is essential for MGL binding, as is Ca(2+) . NMR data were complemented with molecular dynamics simulations and Corcema-ST to establish a 3D view on the molecular recognition process between Gal, GalNAc, and the Tn-presenting glycopeptides and MGL. Gal and GalNAc have a dual binding mode with opposite trend of the main interaction pattern and the differences in affinity can be explained by additional hydrogen bonds and CH-π contacts involving exclusively the NHAc moiety.

UI MeSH Term Description Entries
D008969 Molecular Sequence Data Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories. Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D006020 Glycopeptides Proteins which contain carbohydrate groups attached covalently to the polypeptide chain. The protein moiety is the predominant group with the carbohydrate making up only a small percentage of the total weight. Glycopeptide
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000595 Amino Acid Sequence The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION. Protein Structure, Primary,Amino Acid Sequences,Sequence, Amino Acid,Sequences, Amino Acid,Primary Protein Structure,Primary Protein Structures,Protein Structures, Primary,Structure, Primary Protein,Structures, Primary Protein
D015295 Antigens, Tumor-Associated, Carbohydrate Carbohydrate antigens expressed by malignant tissue. They are useful as tumor markers and are measured in the serum by means of a radioimmunoassay employing monoclonal antibodies. Antigens, Carbohydrate, Tumor-Associated,CA Antigens,Cancer-Associated Carbohydrate Antigens,Carbohydrate Antigens, Tumor-Associated,Tumor-Associated Carbohydrate Antigens,Antigen, Carcinoma-Associated,CA Antigen,CA(Oxford) Antigen,Carcinoma-Associated Antigen,Epitectin,Antigen, CA,Antigen, Carcinoma Associated,Antigens, CA,Antigens, Cancer-Associated Carbohydrate,Antigens, Tumor-Associated Carbohydrate,Cancer Associated Carbohydrate Antigens,Carbohydrate Antigens, Cancer-Associated,Carbohydrate Antigens, Tumor Associated,Carcinoma Associated Antigen,Tumor Associated Carbohydrate Antigens
D056004 Molecular Dynamics Simulation A computer simulation developed to study the motion of molecules over a period of time. Molecular Dynamics Simulations,Molecular Dynamics,Dynamic, Molecular,Dynamics Simulation, Molecular,Dynamics Simulations, Molecular,Dynamics, Molecular,Molecular Dynamic,Simulation, Molecular Dynamics,Simulations, Molecular Dynamics
D018396 Mucin-1 Carbohydrate antigen elevated in patients with tumors of the breast, ovary, lung, and prostate as well as other disorders. The mucin is expressed normally by most glandular epithelia but shows particularly increased expression in the breast at lactation and in malignancy. It is thus an established serum marker for breast cancer. Antigen CA-15-3,CA-15-3 Antigen,Episialin,Epithelial Membrane Antigen,Epithelial Mucin, Polymorphic,Muc1 Mucin,Polymorphic Epithelial Mucin,Antigens, CD227,CA 15-3 Antigen,CA 15.3 Antigen,CD227 Antigen,Antigen CA 15 3,Antigen, CA 15-3,Antigen, CA 15.3,Antigen, CA-15-3,Antigen, CD227,Antigen, Epithelial Membrane,CA 15 3 Antigen,CA-15-3, Antigen,CD227 Antigens,Membrane Antigen, Epithelial,Mucin 1,Mucin, Muc1,Mucin, Polymorphic Epithelial
D019906 Nuclear Magnetic Resonance, Biomolecular NMR spectroscopy on small- to medium-size biological macromolecules. This is often used for structural investigation of proteins and nucleic acids, and often involves more than one isotope. Biomolecular Nuclear Magnetic Resonance,Heteronuclear Nuclear Magnetic Resonance,NMR Spectroscopy, Protein,NMR, Biomolecular,NMR, Heteronuclear,NMR, Multinuclear,Nuclear Magnetic Resonance, Heteronuclear,Protein NMR Spectroscopy,Biomolecular NMR,Heteronuclear NMR,Multinuclear NMR,NMR Spectroscopies, Protein,Protein NMR Spectroscopies,Spectroscopies, Protein NMR,Spectroscopy, Protein NMR
D037181 Lectins, C-Type A class of animal lectins that bind to carbohydrate in a calcium-dependent manner. They share a common carbohydrate-binding domain that is structurally distinct from other classes of lectins. C-Type Lectin Receptor,C-Type Lectins,C-Type Lectin,Lectin, C-Type,Receptors, C-Type Lectin,C Type Lectin,C Type Lectin Receptor,C Type Lectins,C-Type Lectin Receptors,Lectin Receptor, C-Type,Lectin Receptors, C-Type,Lectin, C Type,Lectins, C Type,Receptor, C-Type Lectin,Receptors, C Type Lectin

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