Molecular mechanism of SHP2 activation by PD-1 stimulation

verfasst von

M. Marasco, A. Berteotti, J. Weyershaeuser, N. Thorausch, J. Sikorska, J. Krausze, H. J. Brandt, J. Kirkpatrick, P. Rios, W. W. Schamel, M. Köhn, T. Carlomagno

Abstract

In cancer, the programmed death-1 (PD-1) pathway suppresses T cell stimulation and mediates immune escape. Upon stimulation, PD-1 becomes phosphorylated at its immune receptor tyrosine-based inhibitory motif (ITIM) and immune receptor tyrosine-based switch motif (ITSM), which then bind the Src homology 2 (SH2) domains of SH2-containing phosphatase 2 (SHP2), initiating T cell inactivation. The SHP2-PD-1 complex structure and the exact functions of the two SH2 domains and phosphorylated motifs remain unknown. Here, we explain the structural basis and provide functional evidence for the mechanism of PD-1-mediated SHP2 activation. We demonstrate that full activation is obtained only upon phosphorylation of both ITIM and ITSM: ITSM binds C-SH2 with strong affinity, recruiting SHP2 to PD-1, while ITIM binds N-SH2, displacing it from the catalytic pocket and activating SHP2. This binding event requires the formation of a new inter-domain interface, offering opportunities for the development of novel immunotherapeutic approaches.

Organisationseinheit(en)

Institut für Organische Chemie

Externe Organisation(en)

European Molecular Biology Laboratory (EMBL)
Albert-Ludwigs-Universität Freiburg
Helmholtz-Zentrum für Infektionsforschung GmbH (HZI)
Universitätsklinikum Freiburg

Typ

Artikel

Journal

Science advances

Band

6

Anzahl der Seiten

15

ISSN

2375-2548

Publikationsdatum

31.01.2020

Publikationsstatus

Veröffentlicht

Peer-reviewed

Ja

ASJC Scopus Sachgebiete

Allgemein

Ziele für nachhaltige Entwicklung

SDG 3 – Gute Gesundheit und Wohlergehen

Elektronische Version(en)

https://doi.org/10.1126/sciadv.aay4458 (Zugang: Offen)