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,* and T. Carlomagno,*

Science Advances  31 Jan 2020: Vol. 6, no. 5, eaay4458 DOI: 10.1126/sciadv.aay4458

 

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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.