TeTIR domains define a new class of animal TIR-like NADase effectors in STAND proteins
- 1University of Cologne
Abstract
TIR domains are found in diverse immune signaling proteins and, in several systems, function as NAD+-cleaving enzymes causing or signaling cell death. In plants, TIR domains occur as effector domains in TNL immune receptors, where they are coupled to a central STAND ATPase and a C-terminal repeat domain. Here, we identify TeTIR (TEP1 extended TIR), a previously unrecognized family of TIR-like domains associated with NACHT-type ATPases and C-terminal WD40 or TPR repeat domains. The TeTIR domain of human TEP1 exhibits robust NADase activity comparable to SARM1-TIR, making TEP1 the only other NADase-active TIR-like protein identified in mammals. NADase activity is conserved in TEP1 homologs from diverse eukaryotes. The crystal structure of TEP1 TeTIR reveals an extended TIR-like fold with additional secondary-structure elements and a distinctive RWG-containing loop. Molecular dynamics simulations indicate that the catalytic glutamate contributes to catalysis and the conformational equilibrium of the active-site region, promoting formation of a substrate-accessible state. Structure-guided mutagenesis identifies conserved residues contributing to NAD+ recognition and catalysis, including features distinct from canonical TIR NADases. Expression of isolated TEP1 TeTIR causes NAD+ depletion and cell death in a catalytic-glutamate-dependent manner. TeTIRs thus define a distinct family of animal TIR-like NADases embedded in NACHT-type STAND architectures.
Related
- Novel human liver-tropic AAV variants define transferable domains that markedly enhance the human tropism of AAV7 and AAV8
- Physicochemical properties of native and extruded maize flours in the presence of animal proteins
- Capability of in vitro digestibility methods to predict in vivo digestibility of vegetal and animal proteins
- Quantitative risk assessment of BSE transmission if insects are reared on residual streams containing animal proteins
- Mathematical genomics of SRY proteins and their associated HMG-Box domains across mammals
BibTeX
@misc{hornebeck2026tetir,
title = {{TeTIR domains define a new class of animal TIR-like NADase effectors in STAND proteins}},
author = {J. Hornebeck and R. Ibragimov and N. Oelerich and P. Pfad and J. Jirschitzka and J. M. Gebauer and U. Baumann and T. Hermanns and K. Hofmann},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.21.753143},
url = {https://www.biorxiv.org/content/10.64898/2026.09.21.753143v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - TeTIR domains define a new class of animal TIR-like NADase effectors in STAND proteins
AU - J. Hornebeck
AU - R. Ibragimov
AU - N. Oelerich
AU - P. Pfad
AU - J. Jirschitzka
AU - J. M. Gebauer
AU - U. Baumann
AU - T. Hermanns
AU - K. Hofmann
PY - 2026
DA - 2026/09/21
PB - bioRxiv
DO - 10.64898/2026.09.21.753143
UR - https://www.biorxiv.org/content/10.64898/2026.09.21.753143v1
AB - TIR domains are found in diverse immune signaling proteins and, in several systems, function as NAD+-cleaving enzymes causing or signaling cell death. In plants, TIR domains occur as effector domains in TNL immune receptors, where they are coupled to a central STAND ATPase and a C-terminal repeat domain. Here, we identify TeTIR (TEP1 extended TIR), a previously unrecognized family of TIR-like domains associated with NACHT-type ATPases and C-terminal WD40 or TPR repeat domains. The TeTIR domain of human TEP1 exhibits robust NADase activity comparable to SARM1-TIR, making TEP1 the only other NADase-active TIR-like protein identified in mammals. NADase activity is conserved in TEP1 homologs from diverse eukaryotes. The crystal structure of TEP1 TeTIR reveals an extended TIR-like fold with additional secondary-structure elements and a distinctive RWG-containing loop. Molecular dynamics simulations indicate that the catalytic glutamate contributes to catalysis and the conformational equilibrium of the active-site region, promoting formation of a substrate-accessible state. Structure-guided mutagenesis identifies conserved residues contributing to NAD+ recognition and catalysis, including features distinct from canonical TIR NADases. Expression of isolated TEP1 TeTIR causes NAD+ depletion and cell death in a catalytic-glutamate-dependent manner. TeTIRs thus define a distinct family of animal TIR-like NADases embedded in NACHT-type STAND architectures.
ER -