Abstract
Toll-interleukin-1R resistance (TIR) domains are ubiquitously present in all forms of cellular life. They are most commonly found in signaling proteins, as units responsible for signal-dependent formation of protein complexes that enable amplification and spatial propagation of the signal. A less common function of TIR domains is their ability to catalyze nicotinamide adenine dinucleotide degradation. This survey analyzes 26,414 TIR domains, automatically classified based on group-specific sequence patterns presumably determining biological function, using a statistical approach termed Bayesian partitioning with pattern selection (BPPS). We examine these groups and patterns in the light of available structures and biochemical analyses. Proteins within each of thirteen eukaryotic groups (10 metazoans and 3 plants) typically appear to perform similar functions, whereas proteins within each prokaryotic group typically exhibit diverse domain architectures, suggesting divergent functions. Groups are often uniquely characterized by structural fold variations associated with group-specific sequence patterns and by herein identified sequence motifs defining TIR domain functional divergence. For example, BPPS identifies, in helices C and D of TIRAP and MyD88 orthologs, conserved surface-exposed residues apparently responsible for specificity of TIR domain interactions. In addition, BPPS clarifies the functional significance of the previously described Box 2 and Box 3 motifs, each of which is a part of a larger, group-specific block of conserved, intramolecularly interacting residues.
Highlights
Toll-interleukin-1R resistance (TIR) domains most commonly function as signaling units responsible for transient, signaldependent associations among TIR-containing proteins that enable amplification and spatial propagation of the signal (Pawson and Nash 2003)
TIR domains were first recognized as a region of homology between Drosophila Toll protein and human IL-1 receptor (IL-1R) (Gay and Keith 1991)
Bayesian partitioning with pattern selection (BPPS) classified TIR domains into 36 groups, 6 of which were subdivided further into subgroups (Fig. 1a)
Summary
Toll-interleukin-1R resistance (TIR) domains most commonly function as signaling units responsible for transient, signaldependent associations among TIR-containing proteins that enable amplification and spatial propagation of the signal (Pawson and Nash 2003). The broad phylogenetic distribution of TIR-containing proteins among prokaryotes suggests that bacterial TIR domains mediate a broad spectrum of functions beyond interference with antimicrobial defenses of multicellular organisms. The signaling functions of TIR domains are due to their ability to mutually interact to form transitory oligomeric complexes that typically serve as platforms for recruitment of Immunogenetics (2020) 72:181–203 other signaling components (Kagan et al 2014). These complexes can contain either additional interaction domains, such as the death domain within the adapter TIR protein MyD88, or a catalytic domain capable of transducing the signal spatially (Ferrao et al 2012). TIR domain interactions involve distinct structural surfaces, thereby allowing multiple interactions simultaneously (Toshchakov et al 2011)
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