Structural Evolution of TIR-Domain Signalosomes

Abstract

TIR (Toll/interleukin-1 receptor/resistance protein) domains are cytoplasmic domains widely found in animals and plants, where they are essential components of the innate immune system. A key feature of TIR-domain function in signaling is weak and transient self-association and association with other TIR domains. An additional new role of TIR domains as catalytic enzymes has been established with the recent discovery of NAD⁺-nucleosidase activity by several TIR domains, mostly involved in cell-death pathways. Although self-association of TIR domains is necessary in both cases, the functional specificity of TIR domains is related in part to the nature of the TIR : TIR interactions in the respective signalosomes. Here, we review the well-studied TIR domain-containing proteins involved in eukaryotic immunity, focusing on the structures, interactions and their corresponding functional roles. Structurally, the signalosomes fall into two separate groups, the scaffold and enzyme TIR-domain assemblies, both of which feature open-ended complexes with two strands of TIR domains, but differ in the orientation of the two strands. We compare and contrast how TIR domains assemble and signal through distinct scaffolding and enzymatic roles, ultimately leading to distinct cellular innate-immunity and cell-death outcomes.

Keywords: axon degeneration; cell-death signaling; innate immunity; plant disease resistance; protein structure; protein-protein interactions; signaling by cooperative assembly formation (SCAF); toll/interleukin-1 receptor/resistance protein.

Figure 1

Representative TIR domain structures. TIR domains of the human (TLR1, IL-1R9, MAL, MyD88 and SARM1), lower metazoan Hydra magnipapillata (TRR-2), plant (RPP1 and ROQ1) and bacterial (TcpB) proteins with their corresponding PDB IDs are shown. All the TIR domains show a central core of five β-strands (βA–βE) surrounded by five α-helices (αA–αE). The functionally important BB-loop in each TIR is labeled.

Figure 2

Domain architecture of representative TIR domain-containing proteins. TIR, Toll/interleukin-1 receptor/resistance protein; LRR, leucine-rich repeat; TM, transmembrane; Ig, immunoglobulin; DD, death domain; ID, intermediate domain; NTD, N-terminal domain; RHIM, RIP (receptor-interacting protein) homotypic interaction motif; ARM, armadillo-repeat motif; SAM, sterile alpha motif; DBB, Dof (Drosophila downstream of fibroblast growth factor receptor)/BCAP/BANK (B cell scaffold protein with ankyrin repeats); ANK, ankyrin repeat; NB-ARC, nucleotide-binding adaptor shared by APAF-1 (apoptotic protease-activating factor 1), R proteins and CED-4 (cell death protein 4); CC, coiled coil.

Figure 3

Structural basis of eukaryotic TIR-domain assembly formation. (A) Scaffold TIR-domain assemblies, held together by the BE and BCD interfaces, represented by the TIR domains from MAL, MyD88 and TRR-2. (B) Enzyme TIR-domain assemblies held together by the BE and AE interfaces, represented by the TIR domains from SARM1, RPP1 and ROQ1.

Figure 4

Schematic representation of TIR-domain assemblies. (A) Overview of TIR-domain assemblies. (B) Scaffold TIR-domain assemblies, represented by the structures formed by the TIR domains from human MAL and MyD88. These parallel two-stranded assemblies are held together by the intrastrand BE interfaces, and the interstrand BCD interfaces. (C) Schematic diagram of a single TIR domain, to highlight the BB-loop, BCD, EE and AE surfaces (the diagram does not differentiate the structures of TIR domains in monomeric and signalosome forms). (D) Enzyme TIR-domain assemblies, represented by the structures formed by the TIR domains from human SARM1 and the plant NLRs ROQ1 and RPP1. These antiparallel two-stranded assemblies are held together by the intrastrand BE interfaces and the interstrand AE interfaces.