Structural basis of TIR-domain assembly formation in MyD88/MAL-dependent TLR4 signaling
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia.
- Institute for Glycomics, Griffith University, Southport, QLD 4222, Australia.
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, England.
- Department of Biochemistry, University of Washington, Seattle, Washington, USA.
- Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA.
Toll-like receptor (TLR) signaling represents a key innate immunity response to pathogen products. Recruitment of signaling adapters such as MAL/TIRAP and MyD88 to the receptors requires TIR-domain interactions, which remain structurally elusive. Here we show that MAL TIR domain spontaneously and reversibly forms filaments in vitro, forms a co-filament with TLR4 TIR domain, and induces formation of a MyD88 assembly. A 7 Å resolution cryo-electron microscopy structure reveals a stable MAL proto-filament consisting of two parallel strands of TIR-domain subunits in a BB loop-mediated head-to-tail arrangement. Residues at the interfaces important for the interaction are conserved among different TIR domains. Although large filaments of TLR4, MAL or MyD88 are unlikely to form during signaling in the cell, structure-guided mutagenesis, combined with in vivo interaction assays, demonstrate that the MAL interactions defined within the filament represent a template for a conserved mode of TIR domain interaction involved in both TLR and IL-1R signaling.