Structural basis of NAD+ cleavage activity by mammalian and plant TIR domains

Horsefield S1, Burdett H1, Zhang X2,1, Shi Y3, Manik MK1, Gu W1, Chen J1, Ve T3, Dodds PN2 and Kobe B1

  1. University of Queensland, Brisbane, Qld 4072, Australia.
  2. Agriculture and Food, Commonwealth Scientific and Industrial Research Organisation, Canberra, ACT 2601, Australia.
  3. Institute for Glycomics, Griffith University, Southport, QLD 4222, Australia.

TIR (Toll/interleukin-1 receptor, resistance protein) domains are key components of innate immunity and cell-death signaling pathways in animals and plants. Signaling depends on self-association and homotypic association of TIR domains. We have recently reconstituted large assemblies of the TLR (Toll-like receptor) adaptor TIR domains and determined the structure of the filamentous assembly of TLR adaptor MAL by cryo-electron microscopy. As an unexpected twist, we found that the TIR domains involved in cell-death pathways, including those from the mammalian TLR adaptor SARM, involved in axon degeneration, and those from plant immune receptors (NLRs), possess self-association-dependent NAD+-cleavage activity. Crystal structures of human SARM TIR domain and grapevine NLR Run1 TIR domain in complex with small-molecule ligands shed light on the structural basis of this enzymatic activity. 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.