Topsy-turvy binding of negatively charged homogalacturonan oligosaccharides to galectin-3
Topsy-turvy binding of negatively charged homogalacturonan oligosaccharides to galectin-3
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带负电荷的同型半乳糖醛酸寡糖与半乳糖凝集素 3 的颠倒结合
DOI：
10.1093/glycob/cwaa080
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发表时间：
2020
期刊：
影响因子：
4.3
通讯作者：
Guihua Tai
中科院分区：
文献类型：
--
作者：
Yi Zheng;Jiyong Su;Michelle C Miller;Jie Geng;Xuejiao Xu;Tao Zhang;Maksim Mayzel;Yifa Zhou;Kevin H Mayo;Guihua Tai
半乳糖凝集素-3对许多生理和病理过程至关重要。普遍接受的教条是半乳糖凝集素通过特异性结合细胞表面糖缀合物上的β（1→4）-半乳糖苷表位而在细胞外发挥功能。在这里，我们使用晶体学和NMR光谱来证明带负电荷的同型半乳糖醛酸（HG，α（1→4）-连接-D-半乳糖醛酸（GalA）的线性多糖）与半乳糖凝集素-3碳水化合物识别结构域结合。在GalA环中C6位置的HG羧酸盐要求该糖以非常规的“颠倒”取向结合半乳糖凝集素-3，该取向相对于典型的β-半乳糖苷乳糖的取向翻转约180 °。在这种结合模式中，HG的还原末端GalA β-异头体占据乳糖中非还原末端半乳糖残基的位置。这种新的方向保持与保守的色氨酸和七个最重要的乳糖结合残基的相互作用，尽管具有不同的H-键合相互作用。然而，HG分子取向和新的相互作用具有与乳糖基本相同的热力学结合参数。总的来说，我们的研究提供了一种新型半乳糖凝集素-糖相互作用的结构细节，该相互作用拓宽了配体与Gal-3结合的糖空间，并表明凝集素如何识别细胞表面上的其他带负电荷的多糖，如糖胺聚糖（例如硫酸乙酰肝素）。这一发现影响了我们对半乳糖凝集素介导的生物学功能的理解。
Galectin-3 is crucial to many physiological and pathological processes. The generally accepted dogma is that galectins function extracellularly by binding specifically to β(1→4)-galactoside epitopes on cell surface glycoconjugates. Here, we used crystallography and NMR spectroscopy to demonstrate that negatively charged homogalacturonans (HG, linear polysaccharides of α(1→4)-linked-D-galacturonate (GalA)) bind to the galectin-3 carbohydrate recognition domain. The HG carboxylates at the C6 positions in GalA rings mandate that this saccharide bind galectin-3 in an unconventional, “topsy-turvy” orientation that is flipped by about 180orelative to that of the canonical β-galactoside lactose. In this binding mode, the reducing end GalA β-anomer of HGs takes the position of the nonreducing end galactose residue in lactose. This novel orientation maintains interactions with the conserved tryptophan and seven of the most crucial lactose-binding residues, albeit with different H-bonding interactions. Nevertheless, the HG molecular orientation and new interactions have essentially the same thermodynamic binding parameters as lactose. Overall, our study provides structural details for a new type of galectin–sugar interaction that broadens glycospace for ligand binding to Gal-3 and suggests how the lectin may recognize other negatively charged polysaccharides like glycoaminoglycans (e.g. heparan sulfate) on the cell surface. This discovery impacts on our understanding of galectin-mediated biological function.