Structural Studies of Protein-Carbohydrate Interactions

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The recognition by antibodies of foreign molecules (called antigens) is a key aspect of immunity, but surprisingly little is known about the molecular mechanisms of binding. Interestingly, the immune system treats different kinds of molecules in different ways. For example, when an antibody-bearing cell (called a B-cell) encounters a protein antigen it can chop it into bits to present to T-cells. If a T-cell also recognizes the protein as foreign, it can stimulate B-cells into producing vast quantities of highly-specific tightly-binding antibodies. However, T-cells almost never help this way when a B-cell binds a carbohydrate. This research is focussed on trying to understand at a molecular level how antibodies bind carbohydrates. We have the objectives (1) To determine if the immune system evolved to recognize carbohydrate antigens quickly to make up for the lack of T-cell 'help.' (2) To elucidate the basis for 'cross-reactivity,' where an antibody binds to antigens (in our case carbohydrates) that are chemically similar. (3) We know that there are antibodies specific for carbohydrates that also bind proteins or DNA that 'mimic' carbohydrates, so we aim to determine the molecular mechanism for this 'polyspecificity.' (4) To obtain molecular evidence that by shifting their shapes a single antibody can be specific for completely different antigens. We work in collaboration with scientific groups around the world who have produced antibodies to various important carbohydrate antigens (usually from bacteria) and who have carefully measured the strength of binding and determined the specificities of all of their antibodies. Our investigative method is to generate high-quality crystals of the antibodies by themselves and bound to the carbohydrates. We then use a technique called 'x-ray crystallography' to image the structures of the molecules by measuring how the crystals diffract x-rays, so we can actually see exactly how the antibodies bind their antigens. This research has already expanded what is known about antibody binding, and has the promise of providing dramatic proof of some theories of binding.