Abstract
BackgroundThe human innate immune system uses a system of extracellular Toll-like receptors (TLRs) and intracellular Nod-like receptors (NLRs) to match the appropriate level of immune response to the level of threat from the current environment. Almost all NLRs and TLRs have a domain consisting of multiple leucine-rich repeats (LRRs), which is believed to be involved in ligand binding. LRRs, found also in thousands of other proteins, form a well-defined "horseshoe"-shaped structural scaffold that can be used for a variety of functions, from binding specific ligands to performing a general structural role. The specific functional roles of LRR domains in NLRs and TLRs are thus defined by their detailed surface features. While experimental crystal structures of four human TLRs have been solved, no structure data are available for NLRs.ResultsWe report a quantitative, comparative analysis of the surface features of LRR domains in human NLRs and TLRs, using predicted three-dimensional structures for NLRs. Specifically, we calculated amino acid hydrophobicity, charge, and glycosylation distributions within LRR domain surfaces and assessed their similarity by clustering. Despite differences in structural and genomic organization, comparison of LRR surface features in NLRs and TLRs allowed us to hypothesize about their possible functional similarities. We find agreement between predicted surface similarities and similar functional roles in NLRs and TLRs with known agonists, and suggest possible binding partners for uncharacterized NLRs.ConclusionDespite its low resolution, our approach permits comparison of molecular surface features in the absence of crystal structure data. Our results illustrate diversity of surface features of innate immunity receptors and provide hints for function of NLRs whose specific role in innate immunity is yet unknown.
Highlights
The human innate immune system uses a system of extracellular Toll-like receptors (TLRs) and intracellular Nod-like receptors (NLRs) to match the appropriate level of immune response to the level of threat from the current environment
Homology modeling In order to visualize structures and surface features of leucine-rich repeats (LRRs) domains from human NLRs, homology models were built based on pairwise alignments of NLR amino acid sequences with the sequence of porcine ribonuclease inhibitor (RI), whose X-ray structure (PDB id: 2BNH) was used as a template
Phylogenetic analysis of NLR and TLR leucine-rich repeat domain sequences As a first step, we have performed a phylogenetic analysis of LRR domains in NLRs and TLRs
Summary
The human innate immune system uses a system of extracellular Toll-like receptors (TLRs) and intracellular Nod-like receptors (NLRs) to match the appropriate level of immune response to the level of threat from the current environment. The important role of continuously surveying the environment is played by members of two protein families: extracellular Toll-like receptors (TLRs) and intracellular Nod-like receptors (NLRs), referred to as nucleotide-binding domain- and leucine-rich repeat-containing proteins. From numerous experimental studies it is known that the LRR domains of different TLRs interact with a rather diverse plethora of ligands, from bacterial flagellin and ss/dsRNA to peptidoglycans to imidazoquinioline compounds. By integrating these signals, the TLR receptors sense the microbial state of the immediate environment and define the appropriate level of innate immunity activity
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