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Interaction of SHP-2 SH2 domains with PD-1 ITSM induces PD-1 dimerization and SHP-2 activation.
- Source :
-
Communications Biology . 3/17/2020, Vol. 3 Issue 1, p1-13. 13p. - Publication Year :
- 2020
-
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. 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 23993642
- Volume :
- 3
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Communications Biology
- Publication Type :
- Academic Journal
- Accession number :
- 142294178
- Full Text :
- https://doi.org/10.1038/s42003-020-0845-0