期刊
COMMUNICATIONS BIOLOGY
卷 3, 期 1, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s42003-020-0845-0
关键词
-
资金
- NIH [P50CA101942, P01AI056299, R01CA183605, RO1CA212605, R21AR073494]
Patsoukis et al identify a mechanism by which SHP-2 phosphatase bridges two molecules of the inhibitory checkpoint receptor PD-1, and show this can also induce SHP-2 activation. These data provide insights into the mechanism of SHP-2 activation by PD-1 that may be relevant for its role in T-cell inhibition. 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据