Molecular mechanism of SHP2 activation by PD-1 stimulation

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

doi:10.1126/sciadv.aay4458

Molecular mechanism of SHP2 activation by PD-1 stimulation

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^*

^*Corresponding author for this work

Biosciences

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	eaay4458
Number of pages	15
Journal	Science Advances
Volume	6
Issue number	5
DOIs	https://doi.org/10.1126/sciadv.aay4458
Publication status	Published - 31 Jan 2020

Bibliographical note

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Cell Line
Enzyme Activation
Humans
Multiprotein Complexes/chemistry
Programmed Cell Death 1 Receptor/chemistry
Protein Domains
Protein Tyrosine Phosphatase, Non-Receptor Type 11/chemistry

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title = "Molecular mechanism of SHP2 activation by PD-1 stimulation",

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.",

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author = "M. Marasco and A. Berteotti and J. Weyershaeuser and N. Thorausch and J. Sikorska and J. Krausze and Brandt, \{H. J.\} and J. Kirkpatrick and P. Rios and Schamel, \{W. W.\} and M. K{\"o}hn and T. Carlomagno",

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T1 - Molecular mechanism of SHP2 activation by PD-1 stimulation

AU - Marasco, M.

AU - Berteotti, A.

AU - Weyershaeuser, J.

AU - Thorausch, N.

AU - Sikorska, J.

AU - Krausze, J.

AU - Brandt, H. J.

AU - Kirkpatrick, J.

AU - Rios, P.

AU - Schamel, W. W.

AU - Köhn, M.

AU - Carlomagno, T.

N1 - Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

PY - 2020/1/31

Y1 - 2020/1/31

N2 - 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.

AB - 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.

KW - Cell Line

KW - Enzyme Activation

KW - Humans

KW - Multiprotein Complexes/chemistry

KW - Programmed Cell Death 1 Receptor/chemistry

KW - Protein Domains

KW - Protein Tyrosine Phosphatase, Non-Receptor Type 11/chemistry

UR - https://www.scopus.com/pages/publications/85078977696

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DO - 10.1126/sciadv.aay4458

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JO - Science Advances

JF - Science Advances

IS - 5

M1 - eaay4458

ER -

Molecular mechanism of SHP2 activation by PD-1 stimulation

Abstract

Bibliographical note

UN SDGs

Keywords

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