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首页> 外文期刊>Biochemistry >Sortase Activity Is Controlled by a Flexible Lid in the Pilus Biogenesis Mechanism of Gram-Positive Pathogens,
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Sortase Activity Is Controlled by a Flexible Lid in the Pilus Biogenesis Mechanism of Gram-Positive Pathogens,

机译：在革兰氏阳性病原菌的毛状体生物发生机理中，分选酶活性受柔性盖的控制，

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Pili are surface-linked virulence factors that play key roles in infection establishment in a variety of pathogenic species. In Gram-positive pathogens, pilus formation requires the action of sortases, dedicated transpeptidases that covalently associate pilus building blocks. In Streptococcus pneumoniae, a major human pathogen, all genes required for pilus formation are harbored in a single pathogenicity islet which encodes three structural proteins (RrgA, RrgB, RrgC) and three sortases (SrtC-1, SrtC-2, SrtC-3). RrgB forms the backbone of the streptococcal pilus, to which minor pilins RrgA and RrgC are covalently associated. SrtC-1 is the main sortase involved in polymerization of the RrgB fiber and displays a lid which encapsulates the active site, a feature present in all pilus-related sortases. In this work, we show that catalysis by SrtC-1 proceeds through a catalytic triad constituted of His, Arg, and Cys and that lid instability affects protein fold and catalysis. In addition, we show by thermal shift analysis that lid flexibility can be stabilized by the addition of substrate-like peptides, a feature shared by other periplasmic transpeptidases. We also report the characterization of a trapped acyl-enzyme intermediate formed between SrtC-1 and RrgB. The presence of lid-encapsulated sortases in the pilus biogenesis systems in many Gram-positive pathogens points to a common mechanism of substrate recognition and catalysis that should be taken into consideration in the development of sortase inhibitors.
机译：菌毛是表面相关的毒力因子，在多种病原体的感染建立中起关键作用。在革兰氏阳性病原体中，菌毛的形成需要分选酶的作用，分选酶是共价结合菌毛构件的专用转肽酶。在主要的人类病原体肺炎链球菌中，菌毛形成所需的所有基因都藏在一个致病性小岛中，该小岛编码三种结构蛋白（RrgA，RrgB，RrgC）和三种分选酶（SrtC-1，SrtC-2，SrtC-3）。 。 RrgB形成链球菌菌毛的骨架，未成年人菌毛蛋白RrgA和RrgC与之共价结合。 SrtC-1是参与RrgB纤维聚合的主要分选酶，并显示一个盖住活性位点的盖子，该位点存在于所有菌毛相关分选酶中。在这项工作中，我们表明SrtC-1的催化作用是通过由His，Arg和Cys组成的催化三联体进行的，盖的不稳定性会影响蛋白质的折叠和催化作用。此外，我们通过热位移分析表明，通过添加底物样肽（其他周质转肽酶共有的功能）可以稳定盖子的柔性。我们还报告了SrtC-1和RrgB之间形成的被困酰基酶中间体的表征。在许多革兰氏阳性病原体中，菌毛生物发生系统中存在盖囊化的分选酶，这表明底物识别和催化的共同机制在开发分选酶抑制剂时应予以考虑。

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