PMID- 32064351 OWN - NLM STAT- MEDLINE DCOM- 20201016 LR - 20201016 IS - 2375-2548 (Electronic) IS - 2375-2548 (Linking) VI - 6 IP - 5 DP - 2020 Jan TI - Molecular mechanism of SHP2 activation by PD-1 stimulation. PG - eaay4458 LID - 10.1126/sciadv.aay4458 [doi] LID - eaay4458 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. CI - Copyright (c) 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). FAU - Marasco, M AU - Marasco M AUID- ORCID: 0000-0001-7082-9824 AD - Leibniz University Hannover, Institute of Organic Chemistry and Center for Biomolecular Drug Research, Schneiderberg 38, 30167 Hannover, Germany. FAU - Berteotti, A AU - Berteotti A AD - European Molecular Biology Laboratory, Structural and Computational Biology Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany. AD - European Molecular Biology Laboratory, Genome Biology Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany. FAU - Weyershaeuser, J AU - Weyershaeuser J AUID- ORCID: 0000-0001-8404-3339 AD - Faculty of Biology, Institute of Biology III, University of Freiburg, Schanzlestrasse 18, 79104 Freiburg, Germany. AD - Signalling Research Centers BIOSS and CIBSS, University of Freiburg, Freiburg, Germany. FAU - Thorausch, N AU - Thorausch N AUID- ORCID: 0000-0002-8042-6727 AD - Faculty of Biology, Institute of Biology III, University of Freiburg, Schanzlestrasse 18, 79104 Freiburg, Germany. AD - Signalling Research Centers BIOSS and CIBSS, University of Freiburg, Freiburg, Germany. FAU - Sikorska, J AU - Sikorska J AUID- ORCID: 0000-0002-3836-6708 AD - Helmholtz Centre for Infection Research, Group of Structural Chemistry, Inhoffenstrasse 7, 38124 Braunschweig, Germany. FAU - Krausze, J AU - Krausze J AUID- ORCID: 0000-0001-5333-8046 AD - Leibniz University Hannover, Institute of Organic Chemistry and Center for Biomolecular Drug Research, Schneiderberg 38, 30167 Hannover, Germany. FAU - Brandt, H J AU - Brandt HJ AUID- ORCID: 0000-0002-4067-8591 AD - Faculty of Biology, Institute of Biology III, University of Freiburg, Schanzlestrasse 18, 79104 Freiburg, Germany. AD - Signalling Research Centers BIOSS and CIBSS, University of Freiburg, Freiburg, Germany. FAU - Kirkpatrick, J AU - Kirkpatrick J AUID- ORCID: 0000-0002-9761-3377 AD - Leibniz University Hannover, Institute of Organic Chemistry and Center for Biomolecular Drug Research, Schneiderberg 38, 30167 Hannover, Germany. AD - Helmholtz Centre for Infection Research, Group of Structural Chemistry, Inhoffenstrasse 7, 38124 Braunschweig, Germany. FAU - Rios, P AU - Rios P AUID- ORCID: 0000-0002-9979-5514 AD - European Molecular Biology Laboratory, Genome Biology Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany. AD - Faculty of Biology, Institute of Biology III, University of Freiburg, Schanzlestrasse 18, 79104 Freiburg, Germany. AD - Signalling Research Centers BIOSS and CIBSS, University of Freiburg, Freiburg, Germany. FAU - Schamel, W W AU - Schamel WW AD - Faculty of Biology, Institute of Biology III, University of Freiburg, Schanzlestrasse 18, 79104 Freiburg, Germany. AD - Signalling Research Centers BIOSS and CIBSS, University of Freiburg, Freiburg, Germany. AD - Center of Chronic Immunodeficiency CCI, University Clinics and Medical Faculty, Freiburg, Germany. FAU - Kohn, M AU - Kohn M AUID- ORCID: 0000-0001-8142-3504 AD - European Molecular Biology Laboratory, Genome Biology Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany. AD - Faculty of Biology, Institute of Biology III, University of Freiburg, Schanzlestrasse 18, 79104 Freiburg, Germany. AD - Signalling Research Centers BIOSS and CIBSS, University of Freiburg, Freiburg, Germany. FAU - Carlomagno, T AU - Carlomagno T AUID- ORCID: 0000-0002-2437-2760 AD - Leibniz University Hannover, Institute of Organic Chemistry and Center for Biomolecular Drug Research, Schneiderberg 38, 30167 Hannover, Germany. AD - European Molecular Biology Laboratory, Structural and Computational Biology Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany. AD - Helmholtz Centre for Infection Research, Group of Structural Chemistry, Inhoffenstrasse 7, 38124 Braunschweig, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200131 PL - United States TA - Sci Adv JT - Science advances JID - 101653440 RN - 0 (Multiprotein Complexes) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - EC 3.1.3.48 (PTPN11 protein, human) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11) SB - IM MH - Cell Line MH - Enzyme Activation MH - Humans MH - *Multiprotein Complexes/chemistry/metabolism MH - *Programmed Cell Death 1 Receptor/chemistry/metabolism MH - Protein Domains MH - *Protein Tyrosine Phosphatase, Non-Receptor Type 11/chemistry/metabolism PMC - PMC6994217 EDAT- 2020/02/18 06:00 MHDA- 2020/10/21 06:00 PMCR- 2020/01/31 CRDT- 2020/02/18 06:00 PHST- 2019/06/19 00:00 [received] PHST- 2019/11/22 00:00 [accepted] PHST- 2020/02/18 06:00 [entrez] PHST- 2020/02/18 06:00 [pubmed] PHST- 2020/10/21 06:00 [medline] PHST- 2020/01/31 00:00 [pmc-release] AID - aay4458 [pii] AID - 10.1126/sciadv.aay4458 [doi] PST - epublish SO - Sci Adv. 2020 Jan 31;6(5):eaay4458. doi: 10.1126/sciadv.aay4458. eCollection 2020 Jan.