Logic at the cell surface A major challenge in medical interventions is to target only diseased cells. Although there are biomarkers characteristic of certain cancers, for example, it is unlikely that a single marker can specify a particular cell type. Lajoie et al. addressed this problem by designing protein switches called Co-LOCKR that bind to antigens on the cell surface and activate through a conformational change only when there is a precise combination of antigens. They designed switches that can perform AND, OR, and NOT logic. On the path toward applying this technology, they used Co-LOCKR to direct chimeric antigen receptor T cells to tumor cells expressing specific antigens. Science, this issue p. 1637 Designed proteins compute logic on the cell surface by transforming multiple binding events into a single biological output. Precise cell targeting is challenging because most mammalian cell types lack a single surface marker that distinguishes them from other cells. A solution would be to target cells using specific combinations of proteins present on their surfaces. In this study, we design colocalization-dependent protein switches (Co-LOCKR) that perform AND, OR, and NOT Boolean logic operations. These switches activate through a conformational change only when all conditions are met, generating rapid, transcription-independent responses at single-cell resolution within complex cell populations. We implement AND gates to redirect T cell specificity against tumor cells expressing two surface antigens while avoiding off-target recognition of single-antigen cells, and three-input switches that add NOT or OR logic to avoid or include cells expressing a third antigen. Thus, de novo designed proteins can perform computations on the surface of cells, integrating multiple distinct binding interactions into a single output.

中文翻译：

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设计蛋白质逻辑以通过精确的表面抗原组合靶向细胞

细胞表面的逻辑医学干预的一个主要挑战是仅针对患病细胞。例如，尽管存在某些癌症特有的生物标志物，但单个标志物不太可能指定特定的细胞类型。拉乔伊等人。通过设计称为 Co-LOCKR 的蛋白质开关解决了这个问题，该蛋白质开关与细胞表面的抗原结合，并仅在抗原精确组合时通过构象变化激活。他们设计了可以执行 AND、OR 和 NOT 逻辑的开关。在应用这项技术的过程中，他们使用 Co-LOCKR 将嵌合抗原受体 T 细胞引导至表达特定抗原的肿瘤细胞。科学，这个问题 p。1637 设计的蛋白质通过将多个结合事件转换为单个生物输出来计算细胞表面的逻辑。精确的细胞靶向具有挑战性，因为大多数哺乳动物细胞类型缺乏将它们与其他细胞区分开来的单一表面标记。一种解决方案是使用存在于细胞表面的蛋白质的特定组合来靶向细胞。在这项研究中，我们设计了执行 AND、OR 和 NOT 布尔逻辑运算的共定位依赖性蛋白质开关 (Co-LOCKR)。只有当所有条件都满足时，这些开关才会通过构象变化激活，从而在复杂细胞群中以单细胞分辨率产生快速、不依赖转录的反应。我们实施与门来重定向 T 细胞特异性针对表达两种表面抗原的肿瘤细胞，同时避免单抗原细胞的脱靶识别，以及添加 NOT 或 OR 逻辑的三输入开关，以避免或包括表达第三种抗原的细胞。