Structure-based functional studies for the cellular recognition and cytolytic mechanism of pneumolysin from Streptococcus pneumoniae

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• 作者：Seong Ah Park^a ; Ye Song Park^a ; Seoung Min Bong^b ; Ki Seog Lee^a ; ^{kslee@cup.ac.kr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Pneumolysin ; Cholesterol-dependent cytolysin ; Cellular recognition ; Molecular docking ; X-ray structure
• 刊名：Journal of Structural Biology
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：193
• 期：2
• 页码：132-140
• 全文大小：2740 K

文摘

Cholesterol-dependent cytolysins (CDCs) contribute to various pathogenesis by Gram-positive bacterial pathogens. Among them, pneumolysin (PLY) produced by Streptococcus pneumoniae is a major contributor to pneumococcal infections. Despite numerous studies of the cytolytic mechanism of PLY, little structural information on its interactions with a specific receptor of the cell membrane is available. We report here the first crystal structures of PLY in an apo-form and in a ternary complex with two mannoses at 2.8 Å and 2.5 Å resolutions, respectively. Both structures contained one monomer in an asymmetric unit and were comprised of four discontinuous domains, similar to CDC structures reported previously. The ternary complex structure showed that loop 3 and the undecapeptide region in domain 4 might contribute to cellular recognition by binding to mannose, as a component of a specific cell-surface receptor. Moreover, mutational studies and docking simulations for four residues (Leu431, Trp433, Thr459, and Leu460) in domain 4 indicated that Leu431 and Trp433 in the undecapeptide might be involved in the binding of cholesterol, together with the Thr459–Leu460 pair in loop 1. Our results provide structure-based molecular insights into the interaction of PLY with the target cell membrane, including the binding of mannose and cholesterol.