Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba 305-0801, Japan.
Cell Rep. 2017 Sep 19;20(12):2876-2890. doi: 10.1016/j.celrep.2017.08.080.
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.
东亚型 CagA 相较于西方型 CagA 与胃癌的关联性更为密切。在此我们发现，在发生酪氨酸磷酸化后，东亚型 CagA 所特有的 EPIYA-D 片段与致癌性 SHP2 磷酸酶的 N-SH2 结构域的结合亲和力要比西方型 CagA 所特有的 EPIYA-C 片段高出两个数量级。这种高亲和力的结合是通过 EPIYA-D 中磷酸酪氨酸的+5 位苯丙氨酸与 N-SH2 磷酸肽结合面的一个空洞之间的隐匿性相互作用实现的。此外，西方型 CagA 中 EPIYA-C 的重复，会增加胃癌的风险，使其能够通过 N-SH2 和 C-SH2 与 SHP2 进行二价高亲和力结合。这些强烈的 CagA 结合作用会强制激活 SHP2 的酶活性，赋予细胞致癌特性。从机制上讲，SHP2 的 N-SH2 处于刺激型“松弛”和抑制型“挤压”状态之间的平衡，这种平衡在 CagA 与“松弛”状态发生高亲和力结合后被固定，从而刺激 SHP2。因此，东亚型 CagA 和西方型 CagA 利用不同的机制来实现 SHP2 的失调。
