Structure–Activity Relationships of the Competence Stimulating Peptide in Streptococcus mutans Reveal Motifs Critical for Membrane Protease SepM Recognition and ComD Receptor Activation,ACS Infectious Diseases

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Structure–Activity Relationships of the Competence Stimulating Peptide in Streptococcus mutans Reveal Motifs Critical for Membrane Protease SepM Recognition and ComD Receptor Activation
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2018-07-10 00:00:00 , DOI: 10.1021/acsinfecdis.8b00115
Chowdhury Raihan Bikash ₁ , Sally R. Hamry ₁ , Yftah Tal-Gan ₁

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Streptococcus mutans (S. mutans) is a Gram-positive human pathogen that is one of the major contributors to dental caries, a condition with an economic cost of over $100 billion per year in the United States. S. mutans secretes a 21-amino-acid peptide termed the competence stimulating peptide (21-CSP) to assess its population density in a process termed quorum sensing (QS) and to initiate a variety of phenotypes such as biofilm formation and bacteriocin production. 21-CSP is processed by a membrane bound protease SepM into active 18-CSP, which then binds to the ComD receptor. This study seeks to determine the molecular mechanism that ties 21-CSP:SepM recognition and 18-CSP:ComD receptor binding and to identify QS modulators with distinct activity profiles. To this end, we conducted systematic replacement of the amino acid residues in both 21-CSP and 18-CSP and assessed the ability of the mutated analogs to modulate QS. We identified residues that are important to SepM recognition and ComD receptor binding. Our results shed light on the S. mutans competence QS pathway at the molecular level. Moreover, our structural insights of the CSP signal can be used to design QS-based anti-infective therapeutics against S. mutans.

中文翻译：

变形链球菌中功能刺激肽的结构-活性关系揭示了对于膜蛋白酶SepM识别和ComD受体激活至关重要的基序。

变形链球菌（S. mutans）是革兰氏阳性人类病原体，是龋齿的主要病因之一，在美国，这种病每年造成的经济损失超过1000亿美元。变形链球菌分泌称为能力刺激肽（21-CSP）的21个氨基酸的肽，以在称为群体感应（QS）的过程中评估其种群密度，并启动多种表型，例如生物膜形成和细菌素产生。21-CSP被膜结合蛋白酶SepM加工成活性18-CSP，然后与ComD受体结合。本研究旨在确定将21-CSP：SepM识别与18-CSP：ComD受体结合的分子机制，并鉴定具有不同活性谱的QS调节剂。为此，我们进行了21-CSP和18-CSP中氨基酸残基的系统置换，并评估了突变类似物调节QS的能力。我们鉴定了对SepM识别和ComD受体结合很重要的残基。我们的结果阐明了变形链球菌在分子水平上的能力QS途径。此外，我们对CSP信号的结构洞察力可用于设计基于QS的抗变形链球菌的抗感染治疗剂。

更新日期：2018-07-10

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