title: An unusual dimeric structure and assembly for TLR4 regulator RP105-MD-1.
abstract: RP105-MD-1 modulates the TLR4-MD-2-mediated, innate immune response against bacterial lipopolysaccharide (LPS). The crystal structure of the bovine 1:1 RP105-MD-1 complex bound to a putative endogenous lipid at 2.9 Å resolution shares a similar overall architecture to its homolog TLR4-MD-2 but assembles into an unusual 2:2 homodimer that differs from any other known TLR-ligand assembly. The homodimer is assembled in a head-to-head orientation that juxtaposes the N-terminal leucine-rich repeats (LRRs) of the two RP105 chains, rather than the usual tail-to-tail configuration of C-terminal LRRs in ligand-activated TLR dimers, such as TLR1-TRL2, TLR2-TLR6, TLR3-TLR3 and TLR4-TLR4. Another unusual interaction is mediated by an RP105-specific asparagine-linked glycan, which wedges MD-1 into the co-receptor binding concavity on RP105. This unique mode of assembly represents a new paradigm for TLR complexes and suggests a molecular mechanism for regulating LPS responses.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Sung-il
authors.initials: SI
authors.lastname: Yoon
authors.forename: Minsun
authors.initials: M
authors.lastname: Hong
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000954:Antigens, Surface / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002417:Cattle; D019281:Dimerization; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014961:X-Ray Diffraction
chemical_list: D015703:Antigens, CD; D000954:Antigens, Surface; C092722:CD180 protein, human; C115213:LY86 protein, human; C490500:Ly78 protein, mouse; C113553:Ly86 protein, mouse; D008562:Membrane Glycoproteins; D051197:Toll-Like Receptor 4