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Understanding diversity of human innate immunity receptors: analysis of surface features of leucine-rich repeat domains in NLRs and TLRs.

Istomin AY, Godzik A - BMC Immunol. (2009)

Bottom Line: 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.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Burnham Institute for Medical Research, La Jolla, CA 92037, USA. aistomin@burnham.org

ABSTRACT

Background: 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. 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.

Results: We 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.

Conclusion: Despite 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.

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Hierarchical clustering analysis of amino acid charge distributions within LRR domains of NLRs and TLRs. All notations are the same as in Figure 4.
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Figure 5: Hierarchical clustering analysis of amino acid charge distributions within LRR domains of NLRs and TLRs. All notations are the same as in Figure 4.

Mentions: Figure 5 presents results of a similar clustering analysis of charge distributions. The domain groups with similar hydrophobicity distributions are: RI (ligand: RNase) and NALP9 (ligand unknown); NALP3 (ligands: RNA, small molecules) and NALP2 (ligand unknown); TLR8 (ligands: ssRNA, imidazoquiniolines) and NAIP; TLR3 (ligand: dsRNA), TLR7 (ligands: ssRNA, small molecules), and NALP6 (only 8 LRRs; ligand unknown).


Understanding diversity of human innate immunity receptors: analysis of surface features of leucine-rich repeat domains in NLRs and TLRs.

Istomin AY, Godzik A - BMC Immunol. (2009)

Hierarchical clustering analysis of amino acid charge distributions within LRR domains of NLRs and TLRs. All notations are the same as in Figure 4.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2747839&req=5

Figure 5: Hierarchical clustering analysis of amino acid charge distributions within LRR domains of NLRs and TLRs. All notations are the same as in Figure 4.
Mentions: Figure 5 presents results of a similar clustering analysis of charge distributions. The domain groups with similar hydrophobicity distributions are: RI (ligand: RNase) and NALP9 (ligand unknown); NALP3 (ligands: RNA, small molecules) and NALP2 (ligand unknown); TLR8 (ligands: ssRNA, imidazoquiniolines) and NAIP; TLR3 (ligand: dsRNA), TLR7 (ligands: ssRNA, small molecules), and NALP6 (only 8 LRRs; ligand unknown).

Bottom Line: 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.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Burnham Institute for Medical Research, La Jolla, CA 92037, USA. aistomin@burnham.org

ABSTRACT

Background: 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. 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.

Results: We 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.

Conclusion: Despite 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.

Show MeSH
Related in: MedlinePlus