Maule Andrew F, Wright David P, Weiner Joshua J, Han Lanlan, Peterson Francis C, Volkman Brian F, Silvaggi Nicholas R, Ulijasz Andrew T
Department of Biological Sciences, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, United States of America.
MRC Centre for Molecular Bacteriology and Infection (CMBI), Imperial College London, London, United Kingdom.
PLoS Pathog. 2015 Apr 13;11(4):e1004795. doi: 10.1371/journal.ppat.1004795. eCollection 2015 Apr.
Two-component signaling systems are ubiquitous in bacteria, Archaea and plants and play important roles in sensing and responding to environmental stimuli. To propagate a signaling response the typical system employs a sensory histidine kinase that phosphorylates a Receiver (REC) domain on a conserved aspartate (Asp) residue. Although it is known that some REC domains are missing this Asp residue, it remains unclear as to how many of these divergent REC domains exist, what their functional roles are and how they are regulated in the absence of the conserved Asp. Here we have compiled all deposited REC domains missing their phosphorylatable Asp residue, renamed here as the Aspartate-Less Receiver (ALR) domains. Our data show that ALRs are surprisingly common and are enriched for when attached to more rare effector outputs. Analysis of our informatics and the available ALR atomic structures, combined with structural, biochemical and genetic data of the ALR archetype RitR from Streptococcus pneumoniae presented here suggest that ALRs have reorganized their active pockets to instead take on a constitutive regulatory role or accommodate input signals other than Asp phosphorylation, while largely retaining the canonical post-phosphorylation mechanisms and dimeric interface. This work defines ALRs as an atypical REC subclass and provides insights into shared mechanisms of activation between ALR and REC domains.
双组分信号系统在细菌、古菌和植物中普遍存在，在感知和响应环境刺激方面发挥着重要作用。为了传播信号响应，典型的系统采用一种传感组氨酸激酶，该激酶在保守的天冬氨酸（Asp）残基上使一个接收（REC）结构域磷酸化。尽管已知一些REC结构域缺少这个Asp残基，但目前尚不清楚这些不同的REC结构域有多少存在、它们的功能作用是什么以及在没有保守Asp的情况下它们是如何被调控的。在这里，我们收集了所有已存入的缺少可磷酸化Asp残基的REC结构域，在此将其重新命名为无天冬氨酸接收（ALR）结构域。我们的数据表明，ALR惊人地常见，并且当与更罕见的效应输出相连时会富集。对我们的信息学分析以及现有的ALR原子结构，再结合此处展示的肺炎链球菌ALR原型RitR的结构、生化和遗传数据表明，ALR已经重新组织了它们的活性口袋，转而承担组成型调节作用或容纳除Asp磷酸化之外的输入信号，同时在很大程度上保留了典型的磷酸化后机制和二聚体界面。这项工作将ALR定义为一种非典型的REC亚类，并深入了解了ALR和REC结构域之间共享的激活机制。
