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Cell Rep. 2017 Sep 19;20(12):2876-2890. doi: 10.1016/j.celrep.2017.08.080.

Differential Mechanisms for SHP2 Binding and Activation Are Exploited by Geographically Distinct Helicobacter pylori CagA Oncoproteins.

Author information

1
Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
2
Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba 305-0801, Japan.
3
Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Max Planck-The University of Tokyo Center for Integrative Inflammology, Tokyo 113-0033, Japan.
4
Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba 305-0801, Japan; Department of Materials Structure Science, School of High Energy Accelerator Science, The Graduate University of Advanced Studies, Tsukuba 305-0801, Japan. Electronic address: toshiya.senda@kek.jp.
5
Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan; Max Planck-The University of Tokyo Center for Integrative Inflammology, Tokyo 113-0033, Japan. Electronic address: mhata@m.u-tokyo.ac.jp.

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.

KEYWORDS:

EPIYA motif; East Asian CagA; Helicobacter pylori; SH2 domain; SHP2; Western CagA; allosteric regulation; gastric cancer

PMID:
28930683
DOI:
10.1016/j.celrep.2017.08.080
[Indexed for MEDLINE]
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