Abstract
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.
Highlights
In a changing environment organisms must have means to effectively respond to external stimuli or perish
A typical Two-Component Signaling (TCS) pair consists of a sensor protein, which upon an environmental stimulation will initiate a cellular response by transferring a phosphate group onto a crucial aspartate amino acid within a secondary receiver (REC) protein
Combining computational data with structural, biochemical and genetic examination of a founding member of the Aspartate-Less Receiver (ALR) family, Repressor of Iron Transport Regulator (RitR) from the human pathogen Streptococcus pneumoniae, we demonstrate that ALRs might have evolved to accommodate more diverse environmental signals, while largely retaining their time-tested ancestral post-input signaling mechanisms
Summary
In a changing environment organisms must have means to effectively respond to external stimuli or perish. First described by Zhu et al [12], this so-called “Y/T-coupling” results in a repositioning of the quaternary structure, usually through the α4-α5-α5 interface of the REC protein architecture, to allow the precise alignment of ionic and hydrophobic residues to form the normally observed active homodimer [13,14], a possible alternative dimeric interface centered around the α1-α5 face has been described [15,16]. After these events the C-terminal Effector Domain (ED) [17], which is often a DNA-binding domain but can take the form of many other output modules [4,18], is freed of the physical restraint implemented by close contact with the REC domain to enable downstream signaling [4,15,19]
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