幽门螺杆菌可塑区蛋白的结构与功能机制研究

Helicobacter pylori is one of the most widespread bacterial pathogens of humans, which infects proximately 50% of the world's population. H. pylori infection induces chronic gastric inflammation progressing to a variety of diseases ranging in severity from mild gastritis to peptic ulcers and some forms of gastric cancer.The complicated pathology for various clinical outcomes has not been fully elucidated. Strain-specific genetic diversity has been proposed to be involved in H. pylori's ability to cause different severity of diseases. Genome sequence comparisons revealed the plasticity regions in which nearly half the strain-specific genes of H. pylori are located. Recently, there has been considerable interest in strain-specific plasticity region genes. Studies have suggested that some genes are associated with the pathogenesis of H. pylori related disease. However, little is known about many of the plasticity region genes. Here we have determined the first crystal structure of the plasticy region protein JHP933 and the structural information demonstrated that JHP933 possesses a characteristic nucleotidyltransferase superfamily protein core structure. However, further studies are necessary to in-depth elucidate JHP933's molecular mechanism of action. We will also perform the structural and functional studies of some other important proteins encoded by plasticity region genes of H. pylori. Put together, these structural and functioanl data will contribute significantly to understanding the molecular basis for the role of plasticity region genes in pathogenesis of disease caused by H. pylori, thus help provide better approaches for prevention and cure of the diseases caused by H. pylori.

幽门螺杆菌感染了全世界一半以上的人口，是胃炎，消化性溃疡和胃癌的主要致病原。但是其具体的致病机制还不是很明确。幽门螺杆菌一半以上的特异性基因位于可塑区（plasticity regions）。幽门螺杆菌可塑区基因与其菌株多样性和导致临床病症复杂性和临床转归严重度密切相关，因此吸引了越来越多的关注与研究。 本项目从幽门螺杆菌可塑区的几个重要蛋白入手，通过结构生物学手段结合功能研究方法深入探索蛋白的结构与功能机制。目前，我们已经获得了可塑区蛋白JHP933的晶体结构，并通过结构确定了其基本的核苷酸转移酶功能，但是具体的作用机理还有待更深入的研究阐释。我们还将进行其他可塑区重要蛋白的结构与功能研究，深入揭示这些蛋白的作用机制。综合分析本项目的研究结果，将全面深刻理解和揭示幽门螺杆菌可塑区基因的致病机理以及进化意义，并有助于幽门螺杆菌相关疾病的预防与治疗。

幽门螺杆菌感染了全世界一半以上的人口，是消化性溃疡和胃癌的主要致病原。但是其具体的致病机制还不是很明确。幽门螺杆菌一半以上的特异性基因位于可塑区。幽门螺杆菌可塑区基因与其菌株多样性和导致临床病症复杂性和临床转归严重度密切相关，因此吸引了越来越多的关注与研究。 本项目运用结构生物学手段，解析了幽门螺杆菌可塑区以及致病岛等疾病相关的重要蛋白，包括：HP933；HP933同源蛋白LinA/lincomycin/Mg2+/AMPCPP；CagX；HP0530（CagV）；Cagβ/CagZ 复合体等结构。基于结构，开展了相关的功能研究，深入阐释了蛋白的作用机制。 通过综合分析结构结合功能的研究结果，将全面深刻理解和揭示幽门螺杆菌可塑区基因的致病机理以及进化意义，并有助于幽门螺杆菌相关疾病的预防与治疗。