PMID: 21959264

 

    Legend: Sugar

Title : Crystal structures of mouse and human RP105 / MD-1 complexes reveal unique dimer organization of the toll-like receptor family

Abstract :

1. The Toll-like receptor ( TLR) 4 / MD-2 heterodimer senses lipopolysaccharide (LPS)
2. RP105 (radioprotective 105 kDa), a TLR-related molecule, is similar to TLR4 in that the extracellular leucine-rich repeats leucine-rich repeats associate with MD-1 , the MD-2-like molecule
3. MD-2 has a unique hydrophobic cavity that directly binds to lipid A, the active center of LPS
4. LPS-bound MD-2 opens the secondary interface with TLR4 , leading to dimerization of TLR4 / MD-2
5. 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
6. Little is known, however, about the structure of the RP105 / MD-1 heterodimer or its oligomer
7. Here, we have determined the crystal structures of mouse and human RP105 / MD-1 complexes at 1.9 and 2.8 Å resolutions, respectively
8. Both mouse and human RP105 / MD-1 exhibit dimerization of the 1:1 RP105 / MD-1 complex, demonstrating a novel organization
9. The "m"-shaped 2:2 RP105 / MD-1 complex exhibits an inverse arrangement, with N-termini interacting in the middle
10. 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
11. 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