Structure-guided insights into TIR-mediated bacterial and eukaryotic immunity

Area of Science:

• Molecular Biology
• Immunology
• Biochemistry

Background:

• Toll/interleukin-1 receptor (TIR) domains are crucial signaling molecules in innate immunity.
• Evolution has expanded TIR domain functions beyond immunity to include enzymatic activities.
• These diverse functions are critical for cellular defense mechanisms.

Purpose of the Study:

• To review the functional diversity of TIR domains, focusing on their roles in bacterial antiphage defense.
• To highlight the structural basis of TIR domain function, particularly multimerization.
• To explore conserved topological characteristics across bacterial and eukaryotic TIR domains.

Main Methods:

• Structure-based review of published literature on TIR domain functions.
• Analysis of conserved multimerization and filament formation in TIR domains.
• Comparative analysis of bacterial and eukaryotic TIR domain mechanisms.

Main Results:

• TIR domains exhibit diverse enzymatic activities, including NAD(P) hydrolase, RNA/DNA nuclease, and CN cyclase.
• These activities contribute to cellular defense by generating second messengers or depleting metabolites like NAD+.
• Activated TIR domains consistently form multimers, often in filaments, creating composite active sites.

Conclusions:

• Multimerization, including filament formation, is a conserved topological feature of activated TIR domains across species.
• This conserved characteristic underpins the diverse enzymatic functions of TIR domains in cellular defense.
• Understanding TIR domain structure-function relationships provides insights into innate immunity and antiphage strategies.