title: Crystal structures of mouse and human RP105/MD-1 complexes reveal unique dimer organization of the toll-like receptor family.
abstract: The Toll-like receptor (TLR) 4/MD-2 heterodimer senses lipopolysaccharide (LPS). RP105 (radioprotective 105 kDa), a TLR-related molecule, is similar to TLR4 in that the extracellular leucine-rich repeats associate with MD-1, the MD-2-like molecule. MD-2 has a unique hydrophobic cavity that directly binds to lipid A, the active center of LPS. LPS-bound MD-2 opens the secondary interface with TLR4, leading to dimerization of TLR4/MD-2. MD-1 also has a hydrophobic cavity that accommodates lipid IVa, a precursor of lipid A, suggesting a role for the RP105/MD-1 heterodimer in sensing LPS or related microbial products. Little is known, however, about the structure of the RP105/MD-1 heterodimer or its oligomer. Here, we have determined the crystal structures of mouse and human RP105/MD-1 complexes at 1.9 and 2.8 Å resolutions, respectively. Both mouse and human RP105/MD-1 exhibit dimerization of the 1:1 RP105/MD-1 complex, demonstrating a novel organization. The "m"-shaped 2:2 RP105/MD-1 complex exhibits an inverse arrangement, with N-termini interacting in the middle. Thus, the dimerization interface of RP105/MD-1 is located on the opposite side of the complex, compared to the 2:2 TLR4/MD-2 complex. These results demonstrate that the 2:2 RP105/MD-1 complex is distinct from previously reported TLR dimers, including TLR4/MD-2, TLR1/TLR2, TLR2/TLR6, and TLR3, all of which facilitate homotypic or heterotypic interaction of the C-terminal cytoplasmic signaling domain.
authors.affiliation: Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Umeharu
authors.initials: U
authors.lastname: Ohto
authors.forename: Kensuke
authors.initials: K
authors.lastname: Miyake
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000737:chemistry* / Q000378:metabolism; D000954:Antigens, Surface / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D055503:Protein Multimerization; D051193:Toll-Like Receptors / Q000737:chemistry* / Q000378:metabolism
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; D051193:Toll-Like Receptors