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We will be discussing the structural mechanism of how the Toll-like receptor 5 protein binds to FliC, the monomeric protein responsible for the formation of the bacterial flagellar filament.

Please click on the GIFs to view a larger version.

TLRs

The Toll-like receptor protein family are transmembrane proteins involved in pathogen recognition and signaling of the innate immune system. Primarily found on the surface of macrophages and dendritic cells, their horseshoe-shaped, leucine-rich repeat ectodomains bind to conserved pathogen identifiers (such as lipoproteins, RNA and cell wall peptidoglycans) and initiate an inflammation response. The family of proteins received their name when a researcher exclaimed “Das ist ja toll!” or “That’s great!” upon discovery of underdeveloped fruit fly larvae due to mutations in the gene. (1)

TLR5

This protein is a highly conserved germ-line (2) encoded protein found across vertebrates and is the only protein binding TLR to be conserved from fish to mammals. The agonist of the TLR5 receptor is the bacterial flagella, to which binding leads to recruitment of the MyD88, a critical adaptor of the innate immune system, and the activation of NF-κB, a proinflammatory transcription factor. (3) This will result in the activation of an inflammatory response targeting the flagellated bacteria.

TLR5 is of clinical importance as inflammation and tissue repair has been linked with the development of cancer and TLRs are often highly expressed in tumour cells as the NF-κB factor has an anti-apoptotic effect. (4)

Zebrafish TLR5 was used in this structural study as it was the only ortholog successfully expressed.

TLR5-Flic Binding

Figure A. TLR5-FliC Binding overview

TLR5 binds to the monomeric form of flagellin (FliC in Salmonella), a protein found in a wide variety of gram-negative pathogens, to form a 1:1 heterodimer. Two heterodimers can then associate and form a symmetrical 2:2 tetrameric signaling complex. The binding interfaces and arrangements of the tetramer are completely different from other TLR-ligand interactions, but the two C-terminals of the TLR5 proteins are still placed in close proximity upon flagellin binding, a signaling analogous to other TLRs.