Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
Department of Chemistry, Duke University, Durham, North Carolina 27708, United States.
Cell. 2022 Oct 27;185(22):4206-4215.e11. doi: 10.1016/j.cell.2022.09.021. Epub 2022 Oct 6.
Mucus protects the epithelial cells of the digestive and respiratory tracts from pathogens and other hazards. Progress in determining the molecular mechanisms of mucus barrier function has been limited by the lack of high-resolution structural information on mucins, the giant, secreted, gel-forming glycoproteins that are the major constituents of mucus. Here, we report how mucin structures we determined enabled the discovery of an unanticipated protective role of mucus: managing the toxic transition metal copper. Using two juxtaposed copper binding sites, one for Cu and the other for Cu, the intestinal mucin, MUC2, prevents copper toxicity by blocking futile redox cycling and the squandering of dietary antioxidants, while nevertheless permitting uptake of this important trace metal into cells. These findings emphasize the value of molecular structure in advancing mucosal biology, while introducing mucins, produced in massive quantities to guard extensive mucosal surfaces, as extracellular copper chaperones.
黏液保护消化道和呼吸道的上皮细胞免受病原体和其他危害。在确定黏液屏障功能的分子机制方面取得的进展受到限制，因为缺乏对粘蛋白（即粘液的主要成分，是一种巨大的、分泌型、凝胶形成的糖蛋白）的高分辨率结构信息。在这里，我们报告了我们确定的粘蛋白结构如何使人们发现了粘液的一个意外保护作用：管理有毒的过渡金属铜。利用两个相邻的铜结合位点，一个用于 Cu，另一个用于 Cu，肠道粘蛋白 MUC2 通过阻止无效的氧化还原循环和浪费膳食抗氧化剂来防止铜毒性，同时仍然允许这种重要的痕量金属进入细胞。这些发现强调了分子结构在推进黏膜生物学方面的价值，同时将大量产生以保护广泛黏膜表面的粘蛋白作为细胞外铜伴侣介绍。
