5X7B

Crystal structure of SHP2_SH2-CagA EPIYA_C peptide complex

Summary for 5X7B

• Entry DOI: 10.2210/pdb5x7b/pdb
• Related: 5X7C
• Descriptor: Tyrosine-protein phosphatase non-receptor type 11, CagA (3 entities in total)
• Functional Keywords: helicobacter pylori caga, sh2 domain-containing protein tyrosine phosphatase 2 (shp2), caga polymorphism, hydrolase
• Biological source: Homo sapiens (Human); More
• Cellular location: Cytoplasm : Q06124
• Total number of polymer chains: 3
• Total formula weight: 27844.00

Authors

Senda, M.,Senda, T. (deposition date: 2017-02-24, release date: 2017-09-13, Last modification date: 2024-10-23)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.45 Å)