Division of Hematology-Oncology Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
Department of Medicine Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
Commun Biol. 2020 Mar 17;3(1):128. doi: 10.1038/s42003-020-0845-0.
Programmed cell death-1 (PD-1) inhibits T cell responses. This function relies on interaction with SHP-2. PD-1 has one immunoreceptor tyrosine-based inhibitory motif (ITIM) at Y223 and one immunoreceptor tyrosine-based switch motif (ITSM) at Y248. Only ITSM-Y248 is indispensable for PD-1-mediated inhibitory function but how SHP-2 enzymatic activation is mechanistically regulated by one PD-1 phosphotyrosine remains a puzzle. We found that after PD-1 phosphorylation, SHP-2 can bridge phosphorylated ITSM-Y248 residues on two PD-1 molecules via its amino terminal (N)-SH2 and carboxyterminal (C)-SH2 domains forming a PD-1: PD-1 dimer in live cells. The biophysical ability of SHP-2 to interact with two ITSM-pY248 residues was documented by isothermal titration calorimetry. SHP-2 interaction with two ITSM-pY248 phosphopeptides induced robust enzymatic activation. Our results unravel a mechanism of PD-1: SHP-2 interaction that depends only on ITSM-Y248 and explain how a single docking site within the PD-1 cytoplasmic tail can activate SHP-2 and PD-1-mediated inhibitory function.
程序性细胞死亡受体 1（PD-1）抑制 T 细胞的反应。该功能依赖于与 SHP-2 的相互作用。PD-1 在 Y223 有一个免疫受体酪氨酸抑制基序（ITIM），在 Y248 有一个免疫受体酪氨酸开关基序（ITSM）。只有 ITSM-Y248 对 PD-1 介导的抑制功能是必不可少的，但 PD-1 的一个磷酸酪氨酸如何在机制上调节 SHP-2 的酶激活仍然是一个谜。我们发现，PD-1 磷酸化后，SHP-2 可以通过其氨基端（N）-SH2 和羧基端（C）-SH2 结构域将两个 PD-1 分子上磷酸化的 ITSM-Y248 残基桥接起来，在活细胞中形成 PD-1：PD-1 二聚体。等温滴定微量热法记录了 SHP-2 与两个 ITSM-pY248 残基相互作用的物理能力。SHP-2 与两个 ITSM-pY248 磷酸肽的相互作用诱导了强烈的酶激活。我们的结果揭示了 PD-1：SHP-2 相互作用的一种机制，该机制仅依赖于 ITSM-Y248，并解释了 PD-1 细胞质尾部内的单个对接位点如何激活 SHP-2 和 PD-1 介导的抑制功能。
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