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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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An example of mapping the RI amino acid sequence into structure and of RI surface partitioning. A, Mapping between an LRR sequence motif and the RI structure. RI sequence was searched for the conserved LRR pattern LaaLXL, and 16 LRRs were identified. The residue X (magenta) was then used as a reference to define residues belonging to the inner concave surface (yellow and magenta), N-terminal side (green), C-terminal side (blue), and outer convex surface (red). Mapping between a general LRR motif sequence and the structure of LRR #13 is shown by coloring. B, Full RI surface partitioned into four parts as described above.
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Figure 3: An example of mapping the RI amino acid sequence into structure and of RI surface partitioning. A, Mapping between an LRR sequence motif and the RI structure. RI sequence was searched for the conserved LRR pattern LaaLXL, and 16 LRRs were identified. The residue X (magenta) was then used as a reference to define residues belonging to the inner concave surface (yellow and magenta), N-terminal side (green), C-terminal side (blue), and outer convex surface (red). Mapping between a general LRR motif sequence and the structure of LRR #13 is shown by coloring. B, Full RI surface partitioned into four parts as described above.

Mentions: Finally, from the available structures of other LRR-containing proteins it is known that the aaLXLaa pattern corresponds to a beta-strand in the inner concave surface, which is then followed by a C-terminal side loop, by an alpha-helix on the outside convex surface, and by the N-terminal side loop. This property is very well conserved in numerous LRR-containing proteins, and we have utilized it to improve mapping between LRR sequence and structure. The residue X in the aaLXLaa motif was used as reference residue to define positions of all other residues on the LRR surface (Figure 3A). The next 5 residues are located on the C-terminal side (usually loop conformation), the next 12 residues are located in the outer convex part (usually alpha-helical or loop conformation), and finally the next 5 residues represent the N-terminal side (usually loop conformation). In TLRs, the typical length of the outer part is 9 residues, but there is much variation.


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)

An example of mapping the RI amino acid sequence into structure and of RI surface partitioning. A, Mapping between an LRR sequence motif and the RI structure. RI sequence was searched for the conserved LRR pattern LaaLXL, and 16 LRRs were identified. The residue X (magenta) was then used as a reference to define residues belonging to the inner concave surface (yellow and magenta), N-terminal side (green), C-terminal side (blue), and outer convex surface (red). Mapping between a general LRR motif sequence and the structure of LRR #13 is shown by coloring. B, Full RI surface partitioned into four parts as described above.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: An example of mapping the RI amino acid sequence into structure and of RI surface partitioning. A, Mapping between an LRR sequence motif and the RI structure. RI sequence was searched for the conserved LRR pattern LaaLXL, and 16 LRRs were identified. The residue X (magenta) was then used as a reference to define residues belonging to the inner concave surface (yellow and magenta), N-terminal side (green), C-terminal side (blue), and outer convex surface (red). Mapping between a general LRR motif sequence and the structure of LRR #13 is shown by coloring. B, Full RI surface partitioned into four parts as described above.
Mentions: Finally, from the available structures of other LRR-containing proteins it is known that the aaLXLaa pattern corresponds to a beta-strand in the inner concave surface, which is then followed by a C-terminal side loop, by an alpha-helix on the outside convex surface, and by the N-terminal side loop. This property is very well conserved in numerous LRR-containing proteins, and we have utilized it to improve mapping between LRR sequence and structure. The residue X in the aaLXLaa motif was used as reference residue to define positions of all other residues on the LRR surface (Figure 3A). The next 5 residues are located on the C-terminal side (usually loop conformation), the next 12 residues are located in the outer convex part (usually alpha-helical or loop conformation), and finally the next 5 residues represent the N-terminal side (usually loop conformation). In TLRs, the typical length of the outer part is 9 residues, but there is much variation.

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