A survey of TIR domain sequence and structure divergence

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.

STING cyclic dinucleotide sensing originated in bacteria

“…Instead, closure of oyster STING around 2′,3′-cGAMP re-aligns inter-monomer contacts between the adjacent STING and TIR domains, inducing a downward 4° rotation in TIR domain orientation ( Figure 4b ). We did not observe oyster TIR-STING catalytic NAD + cleavage activity in the presence of cyclic dinucleotides, suggesting additional requirements for enzyme activation or that reorientation of the oyster STING TIR domain may instead facilitate protein–protein interactions similar to the signaling adaptor function of TIR domains in human MyD88 and TRIF ( Extended Data Figure 9b – h ) 26 . These results further explain adaptation of STING in metazoans and provide a molecular mechanism for how STING cyclic dinucleotide sensing is structurally communicated to appended effector modules.…”

Toll-Like Receptors: General Molecular and Structural Biology

“…The superfamily of TIR domain-as the cytoplasmic segment and signaling pathways initiator of TLR biosensors-is composed of a conserved structure involving five parallel strands with β-sheet configuration (βA-βE) within the core center enclosed by five α-helices (αA-αE) on either side, and eight loops bind altogether. These loops are named after their connection to the strands with their related secondary structure [6,37,[90][91][92], e.g., CD loop. The CD loop binds the αC helix to the βD strand (Figure 4) [93].…”

“…The boxes 1 (D-K-YDAF-SY) and 3 (-FWKx-) are conserved in TIR domains belonging to superfamily (TLRs and IL-1Rs) and adaptor protein of MyD88. The box 2 (GYKLCI-RD-PG) is conserved in TLRs and IL-1R, separately; in other words, the conserved sequences are specific to each group, respectively, and not in both of TLRs and IL-1Rs as an entire superfamily [ 89 , 91 , 94 ].…”

COVID-19: The Effect of Host Genetic Variations on Host–Virus Interactions

“…(B) Mouse TLR3 dimer structure with bound dsRNA (left), showing p.Pro554Ser located between two sets of interfacial LRRs (middle) and the pair of disulfide disrupting variants (right). (C) TLR3 TIR domain modeled structure (from ModPipe 132 ) showing p.Met870Val (middle) located within the nonpolar residues cluster specific for Group 3 TIR 133 (right). (D) Select missense variants within TLR3 LRR structural motifs (left) and the TLR3–dsRNA interfacial variant (right).…”

“…TLR3 TIR belongs to Group 3 TIR. 133 Group 3 TIR possesses a distinct cluster of bulky nonpolar residues ( Figure 4 C), and the modeled human TLR3 TIR structure suggests that p.Met870Val is likely to interfere with the nonpolar residue cluster ( Figure 4 C). The TBK1 homodimer structure indicates that gnomAD missense variants p.Arg444Gln and p.Arg547Lys in each protomer are likely to perturb several interfacial hydrogen-bonded interactions and that these variants have the potential to perturb TBK1 function ( Figure 4 E).…”