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An unusual dimeric structure and assembly for TLR4 regulator RP105MD-1

Nature Structural & Molecular Biology volume 18, pages 10281035 (2011) | Download Citation

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.

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Acknowledgements

We thank R.L. Stanfield (The Scripps Research Institute) and Y.S. Choo (Sanford-Burnham Medical Research Institute) for critical comments on the manuscript, R.L. Stanfield (The Scripps Research Institute), H. Tien and D. Marciano (The Joint Center for Structural Genomics) for automated crystal screening, and X. Dai and M.A. Elsliger (The Scripps Research Institute) for expert technical assistance. The work was supported by US National Institutes of Health grant AI042266 (to I.A.W.) and the Skaggs Institute for Chemical Biology. X-ray diffraction datasets were collected at the Stanford Synchrotron Radiation Lightsource beamline 9-2 and the Advanced Photon Source beamline 23ID-B. This is manuscript no. 20749 from The Scripps Research Institute.

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Affiliations

  1. Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.

    • Sung-il Yoon
    • , Minsun Hong
    •  & Ian A Wilson
  2. The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.

    • Ian A Wilson

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Contributions

S.Y. and I.A.W. designed experiments. S.Y. and M.H. conducted experiments. S.Y., M.H. and I.A.W. analyzed data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ian A Wilson.

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https://doi.org/10.1038/nsmb.2106

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