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Phylogenetic variation and polymorphism at the toll-like receptor 4 locus (TLR4).

Smirnova I, Poltorak A, Chan EK, McBride C, Beutler B - Genome Biol. (2000)

Bottom Line: The cytoplasmic domain of the Tlr4 protein is highly variable at the carboxy-terminal end.We suggest that selective evolutionary pressure exerted by microbes expressing structurally distinguishable LPS molecules has produced the high level of variability in the Tlr4 extracellular domain.The highly variable carboxy-terminal region of the cytoplasmic domain is likely to determine the magnitude of the response to LPS within a species.

View Article: PubMed Central - HTML - PubMed

Affiliation: The University of Texas Southwestern Medical Center and the Howard Hughes Medical Institute, 5323 Harry Hines Boulevard, Dallas, Texas 75235-9050, USA.

ABSTRACT

Background: Differences in responses to bacterial surface lipopolysaccharides (LPSs) are apparent between and within mammalian species. It has been shown in mice that resistance to LPS is caused by defects in the Toll-like receptor 4 gene (Tlr4), the product of which is thought to bind LPS and mediate LPS signal transduction in immune system cells.

Results: We have sequenced the Toll-like receptor 4 gene of humans (TLR4; 19.0 kilobases, kb) and mice (Tlr4; 91.7 kb), as well as the coding region and splice junctions of Tlr4 from 35 mouse (Mus musculus) strains, from the chimpanzee and from the baboon. No other discernible genes or regions of interspecies conservation lies close to Tlr4 and, in both humans and mice, flanking sequences and introns are rich in repeats of retroviral origin. Interstrain analyses reveal that Tlr4 is a polymorphic protein and that the extracellular domain is far more variable than the cytoplasmic domain, both among strains and among species. The cytoplasmic domain of the Tlr4 protein is highly variable at the carboxy-terminal end.

Conclusions: We suggest that selective evolutionary pressure exerted by microbes expressing structurally distinguishable LPS molecules has produced the high level of variability in the Tlr4 extracellular domain. The highly variable carboxy-terminal region of the cytoplasmic domain is likely to determine the magnitude of the response to LPS within a species.

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Spline curve illustrating interspecific sequence variation across the Tlr4 protein. A multiple alignment of Tlr4 sequences from three rodent species (mouse, rat and hamster) and three primate species (human, chimpanzee and baboon) was generated using the GCG program Pileup. The number of amino acids observed at each residue was plotted using the program Prism 3.0 (a value of 1 was assigned if a single amino acid was observed in the six species; a value of 5 was assigned if five different amino acids were observed among the six species, and so on). The points were then connected using a cubic spline curve. TM, transmembrane domain. Numbering refers to the human sequence. Where a deletion was introduced by Pileup, a single mismatch was assumed. Where the sequence was truncated, each missing residue was tabulated as a separate mismatch.
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Figure 4: Spline curve illustrating interspecific sequence variation across the Tlr4 protein. A multiple alignment of Tlr4 sequences from three rodent species (mouse, rat and hamster) and three primate species (human, chimpanzee and baboon) was generated using the GCG program Pileup. The number of amino acids observed at each residue was plotted using the program Prism 3.0 (a value of 1 was assigned if a single amino acid was observed in the six species; a value of 5 was assigned if five different amino acids were observed among the six species, and so on). The points were then connected using a cubic spline curve. TM, transmembrane domain. Numbering refers to the human sequence. Where a deletion was introduced by Pileup, a single mismatch was assumed. Where the sequence was truncated, each missing residue was tabulated as a separate mismatch.

Mentions: The human and chimpanzee amino-acid sequences are nearly identical over the interval studied, distinguished by only three substitutions. The baboon sequence is 93.5% identical to the human in the extracellular domain, differs in the transmembrane domain by one substitution out of 30 residues, and differs in the proximal cytoplasmic domain by only one residue in 155. At the carboxyl terminus, however, homology is badly disrupted, so that 16 of the last 21 human residues are not replicated in the baboon protein, which is 13 amino acids shorter than the human protein. Similarly, among rodents, the carboxyl terminus of the protein is the least conserved. Overall, the order of conservation with respect to domain is: proximal cytoplasmic domain > transmembrane domain > extracellular domain > distal cytoplasmic domain (Table2, Figure 4).


Phylogenetic variation and polymorphism at the toll-like receptor 4 locus (TLR4).

Smirnova I, Poltorak A, Chan EK, McBride C, Beutler B - Genome Biol. (2000)

Spline curve illustrating interspecific sequence variation across the Tlr4 protein. A multiple alignment of Tlr4 sequences from three rodent species (mouse, rat and hamster) and three primate species (human, chimpanzee and baboon) was generated using the GCG program Pileup. The number of amino acids observed at each residue was plotted using the program Prism 3.0 (a value of 1 was assigned if a single amino acid was observed in the six species; a value of 5 was assigned if five different amino acids were observed among the six species, and so on). The points were then connected using a cubic spline curve. TM, transmembrane domain. Numbering refers to the human sequence. Where a deletion was introduced by Pileup, a single mismatch was assumed. Where the sequence was truncated, each missing residue was tabulated as a separate mismatch.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC31919&req=5

Figure 4: Spline curve illustrating interspecific sequence variation across the Tlr4 protein. A multiple alignment of Tlr4 sequences from three rodent species (mouse, rat and hamster) and three primate species (human, chimpanzee and baboon) was generated using the GCG program Pileup. The number of amino acids observed at each residue was plotted using the program Prism 3.0 (a value of 1 was assigned if a single amino acid was observed in the six species; a value of 5 was assigned if five different amino acids were observed among the six species, and so on). The points were then connected using a cubic spline curve. TM, transmembrane domain. Numbering refers to the human sequence. Where a deletion was introduced by Pileup, a single mismatch was assumed. Where the sequence was truncated, each missing residue was tabulated as a separate mismatch.
Mentions: The human and chimpanzee amino-acid sequences are nearly identical over the interval studied, distinguished by only three substitutions. The baboon sequence is 93.5% identical to the human in the extracellular domain, differs in the transmembrane domain by one substitution out of 30 residues, and differs in the proximal cytoplasmic domain by only one residue in 155. At the carboxyl terminus, however, homology is badly disrupted, so that 16 of the last 21 human residues are not replicated in the baboon protein, which is 13 amino acids shorter than the human protein. Similarly, among rodents, the carboxyl terminus of the protein is the least conserved. Overall, the order of conservation with respect to domain is: proximal cytoplasmic domain > transmembrane domain > extracellular domain > distal cytoplasmic domain (Table2, Figure 4).

Bottom Line: The cytoplasmic domain of the Tlr4 protein is highly variable at the carboxy-terminal end.We suggest that selective evolutionary pressure exerted by microbes expressing structurally distinguishable LPS molecules has produced the high level of variability in the Tlr4 extracellular domain.The highly variable carboxy-terminal region of the cytoplasmic domain is likely to determine the magnitude of the response to LPS within a species.

View Article: PubMed Central - HTML - PubMed

Affiliation: The University of Texas Southwestern Medical Center and the Howard Hughes Medical Institute, 5323 Harry Hines Boulevard, Dallas, Texas 75235-9050, USA.

ABSTRACT

Background: Differences in responses to bacterial surface lipopolysaccharides (LPSs) are apparent between and within mammalian species. It has been shown in mice that resistance to LPS is caused by defects in the Toll-like receptor 4 gene (Tlr4), the product of which is thought to bind LPS and mediate LPS signal transduction in immune system cells.

Results: We have sequenced the Toll-like receptor 4 gene of humans (TLR4; 19.0 kilobases, kb) and mice (Tlr4; 91.7 kb), as well as the coding region and splice junctions of Tlr4 from 35 mouse (Mus musculus) strains, from the chimpanzee and from the baboon. No other discernible genes or regions of interspecies conservation lies close to Tlr4 and, in both humans and mice, flanking sequences and introns are rich in repeats of retroviral origin. Interstrain analyses reveal that Tlr4 is a polymorphic protein and that the extracellular domain is far more variable than the cytoplasmic domain, both among strains and among species. The cytoplasmic domain of the Tlr4 protein is highly variable at the carboxy-terminal end.

Conclusions: We suggest that selective evolutionary pressure exerted by microbes expressing structurally distinguishable LPS molecules has produced the high level of variability in the Tlr4 extracellular domain. The highly variable carboxy-terminal region of the cytoplasmic domain is likely to determine the magnitude of the response to LPS within a species.

Show MeSH