6ROZ

Structure of the N-SH2 domain of the human tyrosine-protein phosphatase non-receptor type 11 in complex with the phosphorylated immune receptor tyrosine-based switch motif

6ROZ の概要

• エントリーDOI: 10.2210/pdb6roz/pdb
• 分子名称: Tyrosine-protein phosphatase non-receptor type 11, immune receptor tyrosine-based switch motif (ITSM) (2 entities in total)
• 機能のキーワード: phosphatase, inhibitory peptide, signal transducer, src homology-2 domains, cell cycle, itsm, immune receptor tyrosine-based switch motif
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 26335.33

構造登録者

Krausze, J.,Sikorska, J.,Carlomagno, T. (登録日: 2019-05-13, 公開日: 2020-02-19, 最終更新日: 2024-10-23)

主引用文献

Marasco, M.,Berteotti, A.,Weyershaeuser, J.,Thorausch, N.,Sikorska, J.,Krausze, J.,Brandt, H.J.,Kirkpatrick, J.,Rios, P.,Schamel, W.W.,Kohn, M.,Carlomagno, T.
Molecular mechanism of SHP2 activation by PD-1 stimulation.
Sci Adv, 6:eaay4458-eaay4458, 2020

PubMed 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.

PubMed: 32064351
DOI: 10.1126/sciadv.aay4458

実験手法

X-RAY DIFFRACTION (2.89 Å)