title: Toll-like receptor 5 forms asymmetric dimers in the absence of flagellin.
abstract: The structure of full-length human TLR5 determined by electron microscopy single-particle image reconstruction at 26Å resolution shows that TLR5 forms an asymmetric homodimer via ectodomain interactions. The structure shows that like TLR9, TLR5 dimerizes in the absence of ligand. The asymmetry of the dimer suggests that TLR5 may recognize two flagellin molecules cooperatively to establish an optimal flagellin response threshold. A TLR5 homology model was generated and fitted into the electron microscopy structure. All seven predicted N-linked glycosylation sites are exposed on the molecular surface, away from the dimer interface. Glycosylation at the first five sites was confirmed by tandem mass spectrometry. Two aspartate residues proposed to interact with flagellin (Asp294 and Asp366) are sterically occluded by a glycan at position 342. In contrast, the central region of the ectodomains near the dimer interface is unobstructed by glycans. Ligand binding in this region would be consistent with the ligand binding sites of other TLRs.
authors.affiliation: Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: Kaifeng
authors.initials: K
authors.lastname: Zhou
authors.forename: Ryuta
authors.initials: R
authors.lastname: Kanai
authors.forename: Phong
authors.initials: P
authors.lastname: Lee
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Wang
authors.forename: Yorgo
authors.initials: Y
authors.lastname: Modis
mesh_terms: D005408:Flagellin / Q000737:chemistry*; D006031:Glycosylation; D006801:Humans; D008958:Models, Molecular; D010316:Particle Size; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D020836:Protein Structure, Quaternary; D040681:Structural Homology, Protein; D013499:Surface Properties; D051198:Toll-Like Receptor 5 / Q000737:chemistry*
chemical_list: C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D005408:Flagellin