6O0V

Crystal structure of the TIR domain G601P mutant from human SARM1, crystal form 2

Summary for 6O0V

• Entry DOI: 10.2210/pdb6o0v/pdb
• Descriptor: Sterile alpha and TIR motif-containing protein 1, CHLORIDE ION, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (4 entities in total)
• Functional Keywords: axon degeneration, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 65796.67

Authors

Horsefield, S.,Burdett, H.,Zhang, X.,Manik, M.K.,Shi, Y.,Chen, J.,Tiancong, Q.,Gilley, J.,Lai, J.,Gu, W.,Rank, M.,Casey, L.,Ericsson, D.J.,Foley, G.,Hughes, R.O.,Bosanac, T.,von Itzstein, M.,Rathjen, J.P.,Nanson, J.D.,Boden, M.,Dry, I.B.,Williams, S.J.,Staskawicz, B.J.,Coleman, M.P.,Ve, T.,Dodds, P.N.,Kobe, B. (deposition date: 2019-02-17, release date: 2019-09-04, Last modification date: 2024-03-13)

Primary citation

Horsefield, S.,Burdett, H.,Zhang, X.,Manik, M.K.,Shi, Y.,Chen, J.,Qi, T.,Gilley, J.,Lai, J.S.,Rank, M.X.,Casey, L.W.,Gu, W.,Ericsson, D.J.,Foley, G.,Hughes, R.O.,Bosanac, T.,von Itzstein, M.,Rathjen, J.P.,Nanson, J.D.,Boden, M.,Dry, I.B.,Williams, S.J.,Staskawicz, B.J.,Coleman, M.P.,Ve, T.,Dodds, P.N.,Kobe, B.
NAD+cleavage activity by animal and plant TIR domains in cell death pathways.
Science, 365:793-799, 2019

PubMed Abstract: SARM1 (sterile alpha and TIR motif containing 1) is responsible for depletion of nicotinamide adenine dinucleotide in its oxidized form (NAD) during Wallerian degeneration associated with neuropathies. Plant nucleotide-binding leucine-rich repeat (NLR) immune receptors recognize pathogen effector proteins and trigger localized cell death to restrict pathogen infection. Both processes depend on closely related Toll/interleukin-1 receptor (TIR) domains in these proteins, which, as we show, feature self-association-dependent NAD cleavage activity associated with cell death signaling. We further show that SARM1 SAM (sterile alpha motif) domains form an octamer essential for axon degeneration that contributes to TIR domain enzymatic activity. The crystal structures of ribose and NADP (the oxidized form of nicotinamide adenine dinucleotide phosphate) complexes of SARM1 and plant NLR RUN1 TIR domains, respectively, reveal a conserved substrate binding site. NAD cleavage by TIR domains is therefore a conserved feature of animal and plant cell death signaling pathways.

PubMed: 31439792
DOI: 10.1126/science.aax1911

Experimental method

X-RAY DIFFRACTION (2.07 Å)