6o0t
From Proteopedia
Crystal structure of selenomethionine labelled tandem SAM domains (L446M:L505M:L523M mutant) from human SARM1
Structural highlights
FunctionSARM1_HUMAN Negative regulator of MYD88- and TRIF-dependent toll-like receptor signaling pathway which plays a pivotal role in activating axonal degeneration following injury. Promotes Wallerian degeneration an injury-induced axonal death pathway which involves degeneration of an axon distal to the injury site. Can activate neuronal death in response to stress. Regulates dendritic arborization through the MAPK4-JNK pathway. Involved in innate immune response. Inhibits both TICAM1/TRIF- and MYD88-dependent activation of JUN/AP-1, TRIF-dependent activation of NF-kappa-B and IRF3, and the phosphorylation of MAPK14/p38.[1] [2] [3] [4] Publication Abstract from PubMedSARM1 (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. NAD(+) cleavage activity by animal and plant TIR domains in cell death pathways.,Horsefield S, Burdett H, Zhang X, Manik MK, Shi Y, Chen J, Qi T, Gilley J, Lai JS, Rank MX, Casey LW, Gu W, Ericsson DJ, Foley G, Hughes RO, Bosanac T, von Itzstein M, Rathjen JP, Nanson JD, Boden M, Dry IB, Williams SJ, Staskawicz BJ, Coleman MP, Ve T, Dodds PN, Kobe B Science. 2019 Aug 23;365(6455):793-799. doi: 10.1126/science.aax1911. PMID:31439792[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Homo sapiens | Large Structures | Boden M | Bosanac T | Burdett H | Casey L | Chen J | Coleman MP | Deerain N | Dodds PN | Dry IB | Ericsson DJ | Foley G | Gilley J | Gu W | Horsefield S | Hughes RO | Kobe B | Lai J | Manik MK | Nanson JD | Rank M | Rathjen JP | Shi Y | Staskawicz BJ | Tiancong Q | Ve T | Williams SJ | Zhang X | Von Itzstein M
