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

肽，单独或作为调节蛋白的区域，可以控制许多生物过程。体内最大的外部肽库来自膳食蛋白质和肽。已知几种食物肽具有控制氧化应激、炎症、血压升高和免疫功能障碍的生物学特性。然而，这些肽表现出许多生物学效应的分子机制在很大程度上仍然未知。我们的工作已经表明，锌螯合作用部分地负责肽抑制锌依赖性“a distintegrin and metalloproteinase”（ADAM）17的活性，所述锌依赖性“a distintegrin and metalloproteinase”（ADAM）17参与体内肿瘤坏死因子活化和炎症反应的引发。ADAM 17和一种密切相关的蛋白质ADAM 10是称为脱落酶的细胞外金属蛋白酶家族的成员，其激活几种调节蛋白。食物肽与脱落酶的相互作用具有生物学意义，因为螯合锌的肽可以通过肠道转运到内皮细胞和免疫细胞。在那里，肽可以直接与细胞膜结合蛋白或其锌辅因子相互作用。这项发现资助计划的重点是了解锌结合肽与主要锌依赖性脱落酶ADAM 17和ADAM 10的相互作用，这两种酶分别参与炎症和血管形成。在模拟口服/胃肠道通道后，预期肽或其片段诱导细胞中由脱落酶激活的结构构象、功能和下游信号传导途径的变化。本研究的目的是：（1）了解锌结合肽与脱落酶锌辅因子相互作用的结构基础;（2）评价锌-肽相互作用对脱落酶功能的影响;（3）利用细胞模型阐明锌-肽对炎症和血管形成信号通路的分子机制。这项工作将导致对食物肽与锌相互作用的化学基础的重大见解，以及对细胞表面脱落酶及其相关生化途径的生物学影响。它还将支持我的研究计划的长期目标，即了解机制，结构-功能关系和细胞对低剂量食源性肽的反应。在未来五年内，拟议的计划将支持10个高素质的人才（2博士，1硕士，1博士后的生物科学部门的培训。

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.