A trapped catalytic product acts as molecular glue for innate immune signalosome assembly.

The Toll-like receptor 4 (TLR4) TIR domain allosterically activates NAD+ hydrolase activity, and its trapped product adenosine diphosphate ribose stabilizes a composite pocket with TIRAP.

• Why it matters: Animal TIR domains in innate immune receptors have been viewed mainly as scaffolds, leaving unclear how their catalytic activity could directly coordinate adaptor recruitment and signaling assembly.
• What they did: The study characterizes TLR4 TIR domain NADase function as allosterically activated and single-turnover, then shows that adenosine diphosphate ribose is entrapped rather than released to form a stabilizing “molecular glue” with TIRAP.
• The result: This produce-and-trap mechanism nucleates signalosome assembly, linking enzymatic activity to adaptor function as a signaling mode for downstream activation.

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