The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
Nat Commun. 2020 May 13;11(1):2265. doi: 10.1038/s41467-020-16223-7.
The mucosal epithelium secretes a host of protective disulfide-rich peptides, including the trefoil factors (TFFs). The TFFs increase the viscoelasticity of the mucosa and promote cell migration, though the molecular mechanisms underlying these functions have remained poorly defined. Here, we demonstrate that all TFFs are divalent lectins that recognise the GlcNAc-α-1,4-Gal disaccharide, which terminates some mucin-like O-glycans. Degradation of this disaccharide by a glycoside hydrolase abrogates TFF binding to mucins. Structural, mutagenic and biophysical data provide insights into how the TFFs recognise this disaccharide and rationalise their ability to modulate the physical properties of mucus across different pH ranges. These data reveal that TFF activity is dependent on the glycosylation state of mucosal glycoproteins and alludes to a lectin function for trefoil domains in other human proteins.
黏膜上皮细胞分泌大量富含二硫键的保护性肽，包括三叶因子（TFFs）。TFF 增加了黏膜的粘弹性并促进细胞迁移，尽管这些功能的分子机制仍未得到明确界定。在这里，我们证明所有的 TFF 都是二价凝集素，能够识别末端带有 GlcNAc-α-1,4-Gal 二糖的粘蛋白样 O-聚糖。糖苷水解酶降解该二糖可使 TFF 与粘蛋白结合失活。结构、突变和生物物理数据提供了有关 TFF 如何识别这种二糖以及解释它们在不同 pH 范围内调节粘液物理性质的能力的见解。这些数据表明 TFF 活性依赖于黏膜糖蛋白的糖基化状态，并暗示了三叶结构域在其他人类蛋白中具有凝集素功能。
