期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 413, 期 4, 页码 815-825出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2011.09.020
关键词
RP105; MD-1; lipopolysaccharide; MD-2; TLR4
资金
- Japanese Ministry of Education, Culture, Sports, Science and Technology
- Tokyo Foundation for Pharmaceutical Sciences
- Grants-in-Aid for Scientific Research [23121510, 21117002] Funding Source: KAKEN
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 angstrom 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. (C) 2011 Elsevier Ltd. All rights reserved.
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