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Positive selection of Toll-like receptor 2 polymorphisms in two closely related old world monkey species, rhesus and Japanese macaques

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Abstract

Toll-like receptor 2 (TLR2) plays an important role in the recognition of a variety of pathogenic microbes. In the present study, we compared polymorphisms of TLR2 locus in two closely related old world monkey species, rhesus monkey (Macaca mulatta) and Japanese monkey (Macaca fuscata). By nucleotide sequencing of the third exon of TLR2 gene from 21 to 35 respective individuals, we could assign 17 haplotype combinations of 17 coding SNPs of ten non-synonymous and seven synonymous substitutions. A non-synonymous substitution at codon position 326 appeared to be differentially fixed in each species, asparagine for M. mulatta whereas tyrosine for M. fuscata, and may contribute to certain functional properties because it locates in the region contributing to ligand binding and interaction with dimerization partner of TLR2-TLR1 heterodimeric complex. Although TLR2 alleles have diverged to similar extent in both species, they have evolved in significantly different ways; TLR2 of M. fuscata has undergone purifying selection while the membrane-proximal part of the extracellular domain of M. mulatta TLR2 exhibits higher rates of non-synonymous substitutions, indicating a trace of Darwinian positive selection.

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Acknowledgments

This work was supported in part by Japan Initiative for Global Research Network on Infectious Diseases (J-GRID) and the Global Centers of Excellence Program of the Ministry of Education, Culture, Sports, Science and Technology of Japan and by the Cooperation Research Program of Primate Research Institute, Kyoto University, Japan

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Authors and Affiliations

  1. Department of Immunogenetics, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan

    Akiko Takaki, Akiko Yamazaki, Hiroki Shibata, Kenji Hirayama & Michio Yasunami

  2. Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan

    Akiko Takaki, Tomoyuki Maekawa & Michio Yasunami

  3. Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

    Akinori Kimura

  4. Department of Cellular and Molecular Biology, Primate Research Institute, Kyoto University, Kyoto, Japan

    Hirohisa Hirai

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  1. Akiko Takaki
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Correspondence to Michio Yasunami.

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Supplementary Figure 1

The effect of amino acid substitution at position 326 on the binding of peptide portion of Pam3CSK4 ligand to TLR2-TLR1 heterodimer. The optimized molecular structure for ternary complex of macaque TLR2-macaque TLR1 heterodimer and Pam3CSK4 ligand was obtained by homology modeling of a template structure of human TLR2-TLR1 heterodimer bound with Pam3CSK4 (PDB accession # 2Z7X). Two structural models of macaque TLR2-TLR1-Pam3CSK4 for Tyr326 variant (Mafu-Hap3, left panel) and Asn326 variant (Mamu-Hap1, right panel) were compared to illustrate the effect of a single amino acid substitution at position 326. Atoms and covalent bonds are shown by sticks as follows: carbon, gray; oxygen, red; nitrogen, blue; sulfur, yellow; and hydrogen of amine/amide, light gray. Noncovalent electrostatic interactions are shown by green lines. The values are binding energy for respective interactions in kcal/mol. Intra-chain interaction between pi-electron of side chain of tyrosine residue at 326 and CH proton of side chain of aspartic acid at 294 was lost by the change to asparagine at 326. Consequently, some interactions (such as between Phe325 of TLR2 and Ser2 of the ligand) were augmented but others (such as between Asp294 of TLR2 and Lys4 of the ligand) were attenuated. (PPT 222 kb)

Supplementary Figure 2

Interaction maps of Pam3CSK4 ligand to TLR2-TLR1 heterodimer. Interactions between ligand and amino acid residues of TLR heterodimer (A-chain, TLR2 and B-chain, TLR1) were illustrated by 2D depiction layout, where the protein residues are arranged around it in order to indicate spatial proximity and hydrogen bonds. Because of the cutoff value of strength of depiction, the weaker interaction of pi-electron of Phe325 with one of the aliphatic arms of Pam3CSK4 (R1 in Supplementary Figure 1) is not shown in the right panel, TLR2(Asn326)-TLR1-Pam3CSK4. (PPT 2,681 kb)

Supplementary Figure 3

Structural change induced by second substitution of amino acid position 405 in Asn326 variant. The structure of TLR2(Asn326)-TLR1-Pam3CSK4 (Mamu-Hap1, left panels) and that of TLR2(Asn326-Ile405)-TLR1-Pam3CSK4 (right panels) are shown. Amino acid positions are for TLR2 except for 383Gln of TLR1 (as indicated). Amino acid 405, the position of second substitution, is not directly involved in either ligand binding or dimerization interface, but the change results in the clustering of hydrophobic side chains of the TLR2 molecule as illustrated in the right upper panel. (PPT 665 kb)

Supplementary Figure 4

Structural change induced by second substitution of amino acid position 416 in Asn326 variant. The structure of TLR2(Asn326)-TLR1-Pam3CSK4 (Mamu-Hap1, left panel) and that of TLR2(Asn326-Ala416)-TLR1-Pam3CSK4 (right panel) are shown. Amino acid positions are for TLR2 except for 383Gln of TLR1 (as indicated). Amino acid 416, the position of second substitution, is not directly involved in either ligand binding or dimerization interface, but the change results in the lost of intra-chain hydrogen bond between the side chain oxygen of threonine at 416 and backbone nitrogen of threonine at 391. (PPT 433 kb)

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Takaki, A., Yamazaki, A., Maekawa, T. et al. Positive selection of Toll-like receptor 2 polymorphisms in two closely related old world monkey species, rhesus and Japanese macaques. Immunogenetics 64, 15–29 (2012). https://doi.org/10.1007/s00251-011-0556-2

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