CD45 is a cell surface phosphatase that shapes the T cell receptor signaling threshold but does not have a known ligand. A family of adenovirus proteins, including E3/49K, exploits CD45 to evade immunity by binding to the extracellular domain of CD45, resulting in the suppression of T cell signaling. We determined the cryo-EM structure of this complex and found that the E3/49K protein is composed of three immunoglobulin domains assembled as “beads on a string” that compel CD45 into a closely abutted dimer by cross-linking the CD45 D3 domain, leading to steric inhibition of its intracellular phosphatase activity. Inspired by the E3/49K mechanism, we engineered CD45 surrogate ligands that can fine-tune T cell activation by dimerizing CD45 into different orientations and proximities. The adenovirus E3/49K protein has taught us that, despite a lack of a known ligand, CD45 activity can be modulated by extracellular dimerizing ligands that perturb its phosphatase activity and alter T cell responses.

中文翻译：

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使用病毒和工程配体进行方向依赖性 CD45 抑制


CD45 是一种细胞表面磷酸酶，可塑造 T 细胞受体信号阈值，但没有已知的配体。腺病毒蛋白家族（包括 E3/49K）通过与 CD45 的胞外结构域结合，利用 CD45 逃避免疫，从而抑制 T 细胞信号传导。我们确定了该复合物的冷冻电镜结构，发现 E3/49K 蛋白由三个免疫球蛋白结构域组成，组装成“串珠”，通过交联 CD45 D3 结构域迫使 CD45 进入紧密相邻的二聚体，导致其细胞内磷酸酶活性的空间抑制。受 E3/49K 机制的启发，我们设计了 CD45 替代配体，可以通过将 CD45 二聚化成不同的方向和接近度来微调 T 细胞活化。腺病毒 E3/49K 蛋白告诉我们，尽管缺乏已知的配体，但 CD45 活性可以通过细胞外二聚化配体进行调节，这些配体会扰乱其磷酸酶活性并改变 T 细胞反应。