5X7B

Crystal structure of SHP2_SH2-CagA EPIYA_C peptide complex

5X7B の概要

• エントリーDOI: 10.2210/pdb5x7b/pdb
• 関連するPDBエントリー: 5X7C
• 分子名称: Tyrosine-protein phosphatase non-receptor type 11, CagA (3 entities in total)
• 機能のキーワード: helicobacter pylori caga, sh2 domain-containing protein tyrosine phosphatase 2 (shp2), caga polymorphism, hydrolase
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Cytoplasm : Q06124
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 27844.00

構造登録者

Senda, M.,Senda, T. (登録日: 2017-02-24, 公開日: 2017-09-13, 最終更新日: 2024-10-23)

主引用文献

Hayashi, T.,Senda, M.,Suzuki, N.,Nishikawa, H.,Ben, C.,Tang, C.,Nagase, L.,Inoue, K.,Senda, T.,Hatakeyama, M.
Differential Mechanisms for SHP2 Binding and Activation Are Exploited by Geographically Distinct Helicobacter pylori CagA Oncoproteins.
Cell Rep, 20:2876-2890, 2017

PubMed Abstract: Helicobacter pylori East Asian CagA is more closely associated with gastric cancer than Western CagA. Here we show that, upon tyrosine phosphorylation, the East Asian CagA-specific EPIYA-D segment binds to the N-SH2 domain of pro-oncogenic SHP2 phosphatase two orders of magnitude greater than Western CagA-specific EPIYA-C. This high-affinity binding is achieved via cryptic interaction between Phe at the +5 position from phosphotyrosine in EPIYA-D and a hollow on the N-SH2 phosphopeptide-binding floor. Also, duplication of EPIYA-C in Western CagA, which increases gastric cancer risk, enables divalent high-affinity binding with SHP2 via N-SH2 and C-SH2. These strong CagA bindings enforce enzymatic activation of SHP2, which endows cells with neoplastic traits. Mechanistically, N-SH2 in SHP2 is in an equilibrium between stimulatory "relaxed" and inhibitory "squeezed" states, which is fixed upon high-affinity CagA binding to the "relaxed" state that stimulates SHP2. Accordingly, East Asian CagA and Western CagA exploit distinct mechanisms for SHP2 deregulation.

PubMed: 28930683
DOI: 10.1016/j.celrep.2017.08.080

実験手法

X-RAY DIFFRACTION (2.45 Å)