title: Ectodomain Architecture Affects Sequence and Functional Evolution of Vertebrate Toll-like Receptors.
abstract: Toll-like receptors (TLRs) are crucial components of innate immunity that specifically recognize diverse pathogen-associated molecular patterns from pathogens. The continuous hydrogen-bond network (asparagine ladder) formed among the asparagine residues on the concave surfaces of neighboring leucine-rich repeat modules assists in stabilizing the overall shape of TLR ectodomains responsible for ligand recognition. Analysis of 28 types of vertebrate TLRs showed that their ectodomains possessed three types of architectures: a single-domain architecture with an intact asparagine ladder, a three-domain architecture with the ladder interrupted in the middle, and a trans-three-domain architecture with the ladder broken in both termini. Based on a phylogenetic analysis, the three vertebrate TLR architectures arose during early evolution. The 1428 vertebrate TLRs can be divided into eight families based on sequence and structural differences. TLRs ligand specificities are affected by their ectodomain architectures. Three-domain TLRs bind hydrophobic ligands, whereas single-domain and trans-three-domain TLRs mainly recognize hydrophilic ligands. Analysis of 39 vertebrate genomes suggested that the number of single-domain TLR genes in terrestrial vertebrate genomes decreased by half compared to aquatic vertebrate genomes. Single-domain TLR genes underwent stronger purifying selective pressures than three-domain TLR genes in mammals. Overall, ectodomain architecture influences the sequence and functional evolution of vertebrate TLRs.
authors.affiliation: Institute of Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.
authors.forename: Jinlan
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Microbial Technology, School of Life Science, Shandong University, Jinan 250100, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Institute of Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: School of Pharmacy, Central South University, Changsha 410013, China.|Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
authors.forename: Deling
authors.initials: D
authors.lastname: Yin
mesh_terms: D000818:Animals; D019143:Evolution, Molecular; D006801:Humans; D010802:Phylogeny; D000072417:Protein Domains; D013329:Structure-Activity Relationship; D051193:Toll-Like Receptors / Q000737:chemistry* / Q000235:genetics*
chemical_list: D051193:Toll-Like Receptors