Molecular interaction of food-derived zinc-binding peptides with sheddases and their cellular functions

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Peptides, alone or as regions of regulatory proteins, can control many biological processes. The largest pool of external peptides in the body comes from dietary proteins and peptides. Several food peptides are known to have biological properties in controlling oxidative stress, inflammation, raised blood pressure and immune dysfunction. However, the molecular mechanisms by which the peptides exhibit many of their biological effects remain largely unknown. Our work has shown that zinc chelation is partly responsible for the activity of peptides in inhibiting a zinc-dependent “a distintegrin and metalloproteinase” (ADAM)17, which is involved in tumour necrosis factor- activation and initiation of inflammatory reactions in the body. ADAM17 and a closely related protein, ADAM10, are members of a family of extracellular metalloproteases known as sheddases, which activate several regulatory proteins. Food peptide interaction with sheddases has biological significance since peptides that sequester zinc can be transported through the intestine to endothelial and immune cells. There, the peptides can interact directly with the cell membrane-bound proteins or their zinc co-factors. This discovery grant proposal focuses on understanding the interaction of zinc-binding peptides with major zinc-dependent sheddases, ADAM17 and ADAM10, which are involved in inflammation and blood vessel formation, respectively. After simulated oral/gastrointestinal passages, the peptides or their fragments are expected to induce changes in structural conformations, functions and downstream signaling pathways activated by the sheddases in cells. The study objectives are to (1) understand the structural basis of interaction between zinc-binding peptides and zinc co-factor of sheddases; (2) evaluate the implications of the zinc-peptide interaction on the sheddase function; and (3) elucidate the molecular mechanisms of the peptides on inflammation and blood vessel formation signalling pathways using cell models. This work will lead to major insights on the chemical basis of food peptide interaction with zinc, and the resulting biological implications on cell-surface sheddases and their associated biochemical pathways. It will also support the long-term goals of my research program, which are to understand the mechanisms, structure-function relationships, and cellular response to low doses of food-derived peptides. During the next five years, the proposed program will support the training of ten highly qualified personnel (2 PhD, 1 MSc, 1 postdoctoral s bioscience sector.