SHP-2 SH2 结构域与 PD-1 ITSM 的相互作用诱导 PD-1 二聚化和 SHP-2 的激活。

Interaction of SHP-2 SH2 domains with PD-1 ITSM induces PD-1 dimerization and SHP-2 activation.

机构信息

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.

出版信息

Commun Biol. 2020 Mar 17;3(1):128. doi: 10.1038/s42003-020-0845-0.

DOI:10.1038/s42003-020-0845-0

PMID:32184441

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7078208/

Abstract

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.

摘要

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。