Rational Design of a Bifunctional AND-Gate Ligand To Modulate Cell-Cell Interactions.,ACS Synthetic Biology

当前位置： X-MOL 学术 › ACS Synth. Biol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Rational Design of a Bifunctional AND-Gate Ligand To Modulate Cell-Cell Interactions.
ACS Synthetic Biology ( IF 3.7 ) Pub Date : 2019-12-19 , DOI: 10.1021/acssynbio.9b00273
Jungmin Lee _{1,

2} , Andyna Vernet ₂ , Katherine Redfield ₃ , Shulin Lu ₄ , Ionita C Ghiran ₄ , Jeffrey C Way ₂ , Pamela A Silver _{2,

5}

Affiliation

Protein "AND-gate" systems, in which a ligand acts only on cells with two different receptors, direct signaling activity to a particular cell type and avoid action on other cells. In a bifunctional AND-gate protein, the molecular geometry of the protein domains is crucial. Here we constructed a tissue-targeted erythropoietin (EPO) that stimulates red blood cell (RBC) production without triggering thrombosis. The EPO was directed to RBC precursors and mature RBCs by fusion to an anti-glycophorin A antibody V region. Many such constructs activated EPO receptors in vitro and stimulated RBC and not platelet production in mice but nonetheless enhanced thrombosis in mice and caused adhesion between RBCs and EPO-receptor-bearing cells. On the basis of a protein-structural model of the RBC surface, we rationally designed an anti-glycophorin-EPO fusion that does not induce cell adhesion in vitro or enhance thrombosis in vivo. Thus, mesoscale geometry can inform the design of synthetic-biological systems.

中文翻译：

合理设计双功能与门配体来调节细胞间相互作用。

蛋白质“与门”系统，其中配体仅作用于具有两种不同受体的细胞，将信号传导活性引导至特定细胞类型并避免作用于其他细胞。在双功能与门蛋白质中，蛋白质结构域的分子几何形状至关重要。在这里，我们构建了一种组织靶向的促红细胞生成素（EPO），它可以刺激红细胞（RBC）的产生而不引发血栓形成。 EPO 通过与抗血型糖蛋白 A 抗体 V 区融合而针对红细胞前体和成熟红细胞。许多这样的构建体在体外激活EPO受体并刺激小鼠中红细胞而不是血小板的产生，但仍然增强小鼠中的血栓形成并导致红细胞和EPO受体携带细胞之间的粘附。基于红细胞表面的蛋白质结构模型，我们合理设计了一种抗血型糖蛋白-EPO融合物，该融合物在体外不会诱导细胞粘附，在体内不会增强血栓形成。因此，介观几何学可以为合成生物系统的设计提供信息。

更新日期：2019-12-19

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11