金騰川團隊揭示B型鏈球菌成孔蛋白CAMP因子的分子機制
中國科學(xué)技術(shù)大學(xué)生命科學(xué)學(xué)院金騰川課題組和加拿大滑鐵盧大學(xué)Michael Palmer課題組合作，利用X晶體衍射技術(shù)首次解析B型鏈球菌成孔蛋白CAMP因子的晶體結(jié)構(gòu)，并揭示了該毒力因子行使生物學(xué)功能的分子機制。研究成果以“Crystal structure of the Streptococcus agalactiae CAMP factor provides insights into its membrane-permeabilizing activity”為題，于6月8日在線發(fā)表于Journal of Biological Chemistry雜志。
B型鏈球菌是導(dǎo)致孕期/圍產(chǎn)期胎兒嚴重感染性疾病的主要病原菌，其中CAMP因子是B型鏈球菌所分泌的毒力因子（溶血素），它通過跨膜形成孔徑而造成細胞裂解（CAMP反應(yīng)）。CAMP反應(yīng)已經(jīng)發(fā)現(xiàn)70多年并曾經(jīng)廣泛用于臨床檢測B型鏈球菌感染，但CAMP因子跨膜形成孔徑的結(jié)構(gòu)生物學(xué)機理仍不清楚。本研究通過解析CAMP因子的晶體結(jié)構(gòu)，發(fā)現(xiàn)其具有全新的蛋白折疊。進一步確定其N端和C端兩個不同區(qū)域的獨特功能，初步闡述其形成跨膜孔徑的分子機理，從而在分子層次解釋CAMP反應(yīng)這一現(xiàn)象。本項目對篩選抗CAMP毒力因子的藥物有一定理論指導(dǎo)意義，同時對揭示蛋白與生物膜相互作用的本質(zhì)有著很重要的啟示作用。
B型鏈球菌毒力因子CAMP因子的晶體結(jié)構(gòu)
該工作由金騰川課題組和加拿大滑鐵盧大學(xué)Michael Palmer課題組共同合作完成。第一作者為金騰川老師和Eric Brefo-Mensah博士。金騰川老師為通訊作者。
論文鏈接：
http://www.jbc.org/content/early/2018/06/08/jbc.RA118.002336.long
ABSTRACT
Streptococcus agalactiae is an important human opportunistic pathogen that can cause serious health problems, particularly among newborns and older individuals. S. agalactiae contains the CAMP factor, a pore-forming toxin first identified in this bacterium. The CAMP reaction is based on the co-hemolytic activity of the CAMP factor and is commonly used to identify S. agalactiae in the clinic. Closely related proteins are present also in other Gram-positive pathogens. Although the CAMP toxin has been discovered more than a half century ago, no structure from this toxin family has been reported, and the mechanism of action of this toxin remains unclear. Here, we report the first structure of this toxin family, revealing a structural fold composed of 5+3 helix bundles. Further analysis by protein truncation and site-directed mutagenesis indicated that the N-terminal 5 helix bundle is responsible for membrane permeabilization, whereas the C-terminal 3 helix bundle is likely responsible for host receptor binding. Interestingly, the C-terminal domain inhibited the activity of both full-length toxin and its N-terminal domain. Moreover, we observed that the linker region is highly conserved and has a conserved DLxxxDxAT sequence motif. Structurally, this linker region extensively interacted with both terminal CAMP factor domains, and mutagenesis disclosed that the conserved sequence motif is required for CAMP factor’s co-hemolytic activity. In conclusion, our results reveal a unique structure of this bacterial toxin and help clarify the molecular mechanism of its co-hemolytic activity.
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