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The Plasticity of the Carbohydrate Recognition Domain Dictates the Exquisite Mechanism of Binding of Human Macrophage Galactose-Type Lectin |
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| Authors: | Ana Diniz Dr Helena Coelho Dr Jorge S Dias Dr Sandra J van Vliet Prof?Dr Jesús Jiménez-Barbero Prof?Dr Francisco Corzana Prof?Dr Eurico J Cabrita Dr Filipa Marcelo |
| Institution: | 1. UCIBIO, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal
These authors contributed equally to this work.;2. UCIBIO, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal CIC bioGUNE, Bizkaia Technology Park, Building 801A, 48170 Derio, Spain Departament of Organic Chemistry II, Faculty of Science & Technology, University of the Basque Country, Leioa, 48940 Bizkaia, Spain These authors contributed equally to this work.;3. UCIBIO, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal;4. Department of Molecular Cell Biology and Immunology, Amsterdam Infection and Immunity Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, 1007MB Amsterdam, the Netherlands;5. CIC bioGUNE, Bizkaia Technology Park, Building 801A, 48170 Derio, Spain Departament of Organic Chemistry II, Faculty of Science & Technology, University of the Basque Country, Leioa, 48940 Bizkaia, Spain Ikerbasque, Basque Foundation for Science, Maria Diaz de Haro 13, 48009 Bilbao, Spain;6. Departamento de Química, Centro de Investigación en Síntesis Química, Universidad de La Rioja, 26006 Logroño, Spain |
| Abstract: | The human macrophage galactose-type lectin (MGL), expressed on macrophages and dendritic cells (DCs), modulates distinct immune cell responses by recognizing N-acetylgalactosamine (GalNAc) containing structures present on pathogens, self-glycoproteins, and tumor cells. Herein, NMR spectroscopy and molecular dynamics (MD) simulations were used to investigate the structural preferences of MGL against different GalNAc-containing structures derived from the blood group A antigen, the Forssman antigen, and the GM2 glycolipid. NMR spectroscopic analysis of the MGL carbohydrate recognition domain (MGL-CRD, C181-H316) in the absence and presence of methyl α-GalNAc (α-MeGalNAc), a simple monosaccharide, shows that the MGL-CRD is highly dynamic and its structure is strongly altered upon ligand binding. This plasticity of the MGL-CRD structure explains the ability of MGL to accommodate different GalNAc-containing molecules. However, key differences are observed in the recognition process depending on whether the GalNAc is part of the blood group A antigen, the Forssman antigen, or GM2-derived structures. These results are in accordance with molecular dynamics simulations that suggest the existence of a distinct MGL binding mechanism depending on the context of GalNAc moiety presentation. These results afford new perspectives for the rational design of GalNAc modifications that fine tune MGL immune responses in distinct biological contexts, especially in malignancy. |
| Keywords: | tumor-associated carbohydrate antigens immune-related lectins molecular modeling molecular recognition NMR spectroscopy |