Animal TIR domains inform the molecular and structural basis of signaling by plant NLR TIR domains

A large group of plant NLR immune receptors contain TIR (Toll/interleukin-1 receptor, resistance) domains involved in signalling at their N-termini. However, the signalling mechanism has remained unclear. TIR domains are also present in proteins involved in innate immunity and cell-death pathways in animals. We have therefore been able to learn about the molecular mechanisms of by TIR domains by complementary studies of both animal and plant systems. We reconstituted large assemblies of the TLR (Toll-like receptor) adaptor TIR domains and determined the structure of the filamentous assembly of the TLR adaptor MAL by cryo-electron microscopy. We further determined the crystal structure of the TIR domain from the protein SARM1, involved in axon degeneration, a cell-death process operating in neurons that involves cleavage of the dinucleotide NAD+. These studies have informed on the function of plant TIR domains. We have evidence that plant TIR domains can also self-associate though more than one interface. Structural similarities between SARM1 and plant TIR domains led us to demonstrate that plant TIR domains can cleave NAD+, and this activity likely plays a role in their HR function. Our studies unify the mechanism of function of TIR domains as signaling by cooperative assembly formation (SCAF) with prion-like features that leads to the activation of effector enzymes, and show that some TIR domains can themselves function as effector enzymes.