Identification of novel contributions to high-affinity glycoprotein-receptor interactions using engineered ligands.
Identification of novel contributions to high-affinity glycoprotein-receptor interactions using engineered ligands.
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DOI：
10.1016/j.jmb.2009.11.073
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发表时间：
2010-02-26
影响因子：
5.6
通讯作者：
Drickamer K
中科院分区：
文献类型：
--
作者：
Coombs PJ;Harrison R;Pemberton S;Quintero-Martinez A;Parry S;Haslam SM;Dell A;Taylor ME;Drickamer K
工程受体片段和糖蛋白配体采用不同的测定格式已被用来解剖的基础上显着增强的结合两个模型膜受体，树突状细胞特异性细胞间粘附分子3-抓取非整联蛋白（DC-SIGN）和巨噬细胞半乳糖凝集素，糖蛋白配体相比，简单的糖。这些方法使得量化两个主要因素的重要性成为可能，这两个因素结合联合收割机将单个碳水化合物识别结构域（CRD）对糖蛋白配体的亲和力提高了100至300倍。首先，单个CRD内延伸结合位点的存在可以增强与分支聚糖的相互作用，导致亲和力增加5倍至20倍。其次，聚糖在糖蛋白表面的呈递使亲和力增加15至20倍，这可能是由于与蛋白质表面的低特异性相互作用或聚糖构象的限制。相反，当避免溶液相网络化时，由于聚糖的多个分支与这些受体的寡聚体形式中的多个CRD结合而引起的增强是最小的，并且受体寡聚体与单个糖蛋白上的多个聚糖的结合仅对总体亲和力做出两倍贡献。因此，在这些情况下，单个糖蛋白与单个受体寡聚体的多价相互作用在实现高亲和力方面具有有限的作用。这些发现，结合膜受体的几何形状的考虑，是一致的想法，进一步增强结合多价糖蛋白配体需要多个受体寡聚体与配体的相互作用。
Engineered receptor fragments and glycoprotein ligands employed in different assay formats have been used to dissect the basis for the dramatic enhancement of binding of two model membrane receptors, dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) and the macrophage galactose lectin, to glycoprotein ligands compared to simple sugars. These approaches make it possible to quantify the importance of two major factors that combine to enhance the affinity of single carbohydrate-recognition domains (CRDs) for glycoprotein ligands by 100-to 300-fold. First, the presence of extended binding sites within a single CRD can enhance interaction with branched glycans, resulting in increases of fivefold to 20-fold in affinity. Second, presentation of glycans on a glycoprotein surface increases affinity by 15-to 20-fold, possibly due to low-specificity interactions with the surface of the protein or restriction in the conformation of the glycans. In contrast, when solution-phase networking is avoided, enhancement due to binding of multiple branches of a glycan to multiple CRDs in the oligomeric forms of these receptors is minimal and binding of a receptor oligomer to multiple glycans on a single glycoprotein makes only a twofold contribution to overall affinity. Thus, in these cases, multivalent interactions of individual glycoproteins with individual receptor oligomers have a limited role in achieving high affinity. These findings, combined with considerations of membrane receptor geometry, are consistent with the idea that further enhancement of the binding to multivalent glycoprotein ligands requires interaction of multiple receptor oligomers with the ligands.
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影响因子：
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