An immune response to bacterial invasion
Ian Wilson group (The Scripps Research Institute) and collaborators
The group of Ian Wilson at The Scripps Research Institute
produced important structural work on the immune response to bacterial
infection. The vertebrate immune system senses invasion of diverse types of
flagellated bacteria using Toll-like receptor 5 (TLR5). TLR5 interacts with
a flagellin protein that constitutes bacterial flagella, subsequently
triggering the first line of defense to clear flagellated pathogens from our
bodies. It is notoriously difficult to work with TLR5, but the Wilson group
managed to solve the 2.47-Å crystal structure of a complex between the
N-terminal fragment of zebrafish TLR5 and the Salmonella flagellin D1-D2-D3
domains. TLR5 forms a 2:2 complex with flagellin via homodimerization of two
copies of 1:1 TLR5-flagellin heterodimers. TLR5 makes specific polar
contacts with highly conserved residues in the D1 domain of flagellin, which
provides an explanation for activation of TLR5 signaling by a variety of
flagellins. The assembly of two TLR5 chains in the complex in a tail-to-tail
orientation resembles other TLRs that bind non-protein ligands, in which the
proximal C-terminal regions in the middle of the complex initiate signaling.
Structural information on the TLR5-flagellin interaction at atomic resolution
provides valuable insights into development of novel vaccine adjuvants and
advancement of therapeutic applications for hyper-inflammatory diseases.
Figure: Crystal structure of the 2:2
TLR5-flagellin complex. Two basic units of 1:1 heterodimers (TLR5-flagellin
and TLR5'-flagellin') assemble into a 2:2 complex, organizing two TLR5 chains
in a tail-to-tail orientation.
Yoon, SI, Kurnasov, O, Natarajan, V, Hong, M, Gudkov, AV, Osterman, AL,
Wilson, IA. Structural basis of TLR5-flagellin recognition and signaling,
Science 335, 859-864 (2012).