Gestwicki J E, Strong L E, Kiessling L L
Department of Chemistry, University of Wisconsin-Madison, 53706, USA.
Chem Biol. 2000 Aug;7(8):583-91. doi: 10.1016/s1074-5521(00)00002-8.
Multivalent ligands have been used previously to investigate the role of ligand valency and receptor clustering in eliciting biological responses. Studies of multivalent ligand function, however, typically have employed divalent ligands or ligands of undefined valency. How cells respond to multivalent ligands of distinct valencies, which can cluster a signaling receptor to different extents, has never been examined. The chemoreceptors, which mediate chemotactic responses in bacteria, are localized, and clustering has been proposed to play a role in their function. Using multivalent ligands directed at the chemoreceptors, we hypothesized that we could exploit ligand valency to control receptor occupation and clustering and, ultimately, the cellular response.
To investigate the effects of ligand valency on the bacterial chemotactic response, we generated a series of linear multivalent arrays with distinct valencies by ring-opening metathesis polymerization. We report that these synthetic ligands elicit bacterial chemotaxis in both Escherichia coli and Bacillus subtilis. The chemotactic response depended on the valency of the ligand; the response of the bacteria can be altered by varying chemoattractant ligand valency. Significantly, these differences in chemotactic responses were related to the ability of the multivalent ligands to cluster chemoreceptors at the plasma membrane.
Our results demonstrate that ligand valency can be used to tune the chemotactic responses of bacteria. This mode of regulation may arise from changes in receptor occupation or changes in receptor clustering or both. Our data implicate changes in receptor clustering as one important mechanism for altering cellular responses. Given the diverse events modulated by changes in the spatial proximity of cell surface receptors, our results suggest a general strategy for tuning biological responses.
多价配体此前已被用于研究配体价态和受体聚集在引发生物学反应中的作用。然而，多价配体功能的研究通常采用二价配体或价态不明确的配体。细胞如何对不同价态的多价配体作出反应，这些配体能够在不同程度上使信号受体聚集，此前从未有人研究过。介导细菌趋化反应的化学感受器是定位的，并且有人提出聚集在其功能中起作用。通过针对化学感受器的多价配体，我们假设我们可以利用配体价态来控制受体占据和聚集，并最终控制细胞反应。
为了研究配体价态对细菌趋化反应的影响，我们通过开环易位聚合生成了一系列具有不同价态的线性多价阵列。我们报告这些合成配体在大肠杆菌和枯草芽孢杆菌中均能引发细菌趋化作用。趋化反应取决于配体的价态；通过改变趋化剂配体价态可以改变细菌的反应。重要的是，这些趋化反应的差异与多价配体在质膜上使化学感受器聚集的能力有关。
我们的结果表明配体价态可用于调节细菌的趋化反应。这种调节模式可能源于受体占据的变化或受体聚集的变化或两者皆有。我们的数据表明受体聚集的变化是改变细胞反应的一种重要机制。鉴于细胞表面受体空间接近度变化所调节的各种事件，我们的结果提示了一种调节生物学反应的通用策略。
