The Helicobacter pylori adhesin protein HopQ exploits the dimer interface of human CEACAMs to facilitate translocation of the oncoprotein CagA
The Helicobacter pylori adhesin protein HopQ exploits the dimer interface of human CEACAMs to facilitate translocation of the oncoprotein CagA
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DOI：
10.15252/embj.201798664
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发表时间：
2018-07-02
期刊：
影响因子：
11.4
通讯作者：
Sundberg, Eric J.
中科院分区：
文献类型：
--
作者：
Bonsor, Daniel A.;Zhao, Qing;Sundberg, Eric J.
世界上一半的人口感染幽门螺杆菌，而编码CAG IV型分泌系统的菌株将癌蛋白CagA注射到宿主胃上皮细胞中，这些菌株与癌症水平升高有关。CagA在宿主细胞中的转运依赖于Hp粘附素蛋白HopQ和人CEACAMs之间的相互作用。在这里，我们展示了几个HopQ-CEACAM复合物和CEACAM的单体和二聚体形式的高分辨结构，证实了HopQ使用耦合的折叠和结合机制来参与CEACAM识别的典型CEACAM二聚化界面。通过将突变与生物物理和功能分析相结合，我们表明HopQ和CEACAMS本身识别CEACAM的模式截然不同。我们的数据描述了微生物利用宿主CEACAM进行感染的精确分子机制，并使未来能够开发新型癌蛋白转位抑制剂和幽门螺杆菌特异性抗菌剂。
Helicobacter pylori infects half of the world's population, and strains that encode the cag type IV secretion system for injection of the oncoprotein CagA into host gastric epithelial cells are associated with elevated levels of cancer. CagA translocation into host cells is dependent on interactions between the H. pylori adhesin protein HopQ and human CEACAMs. Here, we present high-resolution structures of several HopQ-CEACAM complexes and CEACAMs in their monomeric and dimeric forms establishing that HopQ uses a coupled folding and binding mechanism to engage the canonical CEACAM dimerization interface for CEACAM recognition. By combining mutagenesis with biophysical and functional analyses, we show that the modes of CEACAM recognition by HopQ and CEACAMs themselves are starkly different. Our data describe precise molecular mechanisms by which microbes exploit host CEACAMs for infection and enable future development of novel oncoprotein translocation inhibitors and H. pylori-specific antimicrobial agents.