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TLR4 regulation: heads or tails?

SBKB [doi:10.1038/sbkb.2011.41]
Featured Article - October 2011
Short description: The crystal structure of the TLR4 regulator RP105–MD-1 reveals a unique head-to-head conformation and provides a glimpse into the mechanism of TLR4 regulation.

The 2:2 sRP105–MD-1 complex (PDB entry 3RG1) with the individual monomers that comprise the complex labeled “a” and “b”. Reprinted from 1 .

An early and crucial step in the initiation of innate immunity is the recognition of conserved motifs on pathogens by pattern-recognition receptors, including Toll-like receptors (TLRs). To respond to the bacterial antigen lipopolysaccharide (LPS), TLR4 requires the adaptor protein MD-2. Like other TLRs, which dimerize upon ligand binding, LPS-activated TLR4–MD-2 forms a homodimer of two TLR4–MD-2 'blocks' that juxtaposes the two C-terminal Toll-IL-1R (TIR) domains in a 'tail-to-tail' conformation that is characteristic of signaling-competent TLRs. The TLR-like protein RP105 lacks a TIR domain but is phylogenetically similar to TLR4, and requires the adaptor protein MD-1. Although unlikely to signal directly, RP105 regulates other TLRs, including TLR4–MD-2.

To delve into the mechanism by which RP105–MD-1 regulates TLR4, Wilson and colleagues have solved the crystal structure of the RP105–MD-1 homodimeric complex at 2.9-Å resolution. Owing to similarity between RP105–MD-1 and their respective counterparts, TLR4 and MD-2, it was generally assumed that the RP105–MD-1 complex would adopt a similar structure. Indeed, the primary RP105–MD-1 'block' was structurally similar to TLR4–MD-2, although a novel glycan-mediated interface was identified.

The conformation of the homodimer, however, was a unique 'head-to-head' conformation formed by two RP105–MD-1 units. The three homodimerization surfaces identified by the crystal structure and validated by mutagenesis implicated adjacent MD-1 regions in engaging opposite faces of the RP105 leucine-rich repeat domains, bringing together the two N-terminal RP105 'heads'. This is in stark contrast to the 'tail-to-tail' TLR4–MD-2 tetrameric complex, in which disparate regions of MD-2 interact with spatially distinct TLR4 surfaces.

This unusual structure, never previously reported in TLR signaling, has exciting mechanistic implications for TLR4 regulation. One scenario the authors propose is that, because distinct surfaces are involved in forming the RP105–MD-1 homodimer and the TLR4–MD-2 homodimer, the residues homologous to the TLR4–MD-2 homodimerization interface may engage the equivalent surface on free TLR4–MD-2 units. Such a heterologous interaction could both inhibit LPS binding to TLR4–MD-2 and block homodimerization of TLR4–MD-2. The unexpected findings of this study open up compelling new research avenues, such as defining the inhibitory mechanism and determining the role of LPS binding.

Erin Bekes

References

  1. S.I. Yoon et al. An unusual dimeric structure and assembly for TLR4 regulator RP105–MD-1.
    Nat. Struct. Mol. Biol. 18, 1028–1035 (2011). doi:10.1038/nsmb.2106

Structural Biology Knowledgebase ISSN: 1758-1338
Funded by a grant from the National Institute of General Medical Sciences of the National Institutes of Health