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| | <StructureSection load='7lcz' size='340' side='right'caption='[[7lcz]], [[Resolution|resolution]] 1.65Å' scene=''> | | <StructureSection load='7lcz' size='340' side='right'caption='[[7lcz]], [[Resolution|resolution]] 1.65Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[7lcz]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Drome Drome]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LCZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LCZ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7lcz]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Drosophila_melanogaster Drosophila melanogaster]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LCZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LCZ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NMN:BETA-NICOTINAMIDE+RIBOSE+MONOPHOSPHATE'>NMN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.65Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Sarm, Ect4, CG43119 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=7227 DROME])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NMN:BETA-NICOTINAMIDE+RIBOSE+MONOPHOSPHATE'>NMN</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/ADP-ribosyl_cyclase/cyclic_ADP-ribose_hydrolase ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.2.6 3.2.2.6] </span></td></tr> | + | |
| | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7lcz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lcz OCA], [https://pdbe.org/7lcz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lcz RCSB], [https://www.ebi.ac.uk/pdbsum/7lcz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lcz ProSAT]</span></td></tr> | | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7lcz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lcz OCA], [https://pdbe.org/7lcz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lcz RCSB], [https://www.ebi.ac.uk/pdbsum/7lcz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lcz ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/SARM1_DROME SARM1_DROME]] NAD(+) hydrolase, which plays a key role in axonal degeneration following injury by regulating NAD(+) metabolism (PubMed:22678360, PubMed:28334607). Acts as a negative regulator of MYD88- and TRIF-dependent toll-like receptor signaling pathway by promoting Wallerian degeneration, an injury-induced form of programmed subcellular death which involves degeneration of an axon distal to the injury site (PubMed:22678360). Wallerian degeneration is triggered by NAD(+) depletion: in response to injury, it is activated and catalyzes cleavage of NAD(+) into ADP-D-ribose (ADPR), cyclic ADPR (cADPR) and nicotinamide; NAD(+) cleavage promoting axon destruction (PubMed:22678360, PubMed:28334607, PubMed:31439792). Involved in the down-regulation of the tracheal immune response to Gram-negative bacteria (PubMed:22022271). This is likely by mediating Tollo signaling in the tracheal epithelium (PubMed:22022271).<ref>PMID:22022271</ref> <ref>PMID:22678360</ref> <ref>PMID:28334607</ref> <ref>PMID:31439792</ref>
| + | [https://www.uniprot.org/uniprot/SARM1_DROME SARM1_DROME] NAD(+) hydrolase, which plays a key role in axonal degeneration following injury by regulating NAD(+) metabolism (PubMed:22678360, PubMed:28334607). Acts as a negative regulator of MYD88- and TRIF-dependent toll-like receptor signaling pathway by promoting Wallerian degeneration, an injury-induced form of programmed subcellular death which involves degeneration of an axon distal to the injury site (PubMed:22678360). Wallerian degeneration is triggered by NAD(+) depletion: in response to injury, it is activated and catalyzes cleavage of NAD(+) into ADP-D-ribose (ADPR), cyclic ADPR (cADPR) and nicotinamide; NAD(+) cleavage promoting axon destruction (PubMed:22678360, PubMed:28334607, PubMed:31439792). Involved in the down-regulation of the tracheal immune response to Gram-negative bacteria (PubMed:22022271). This is likely by mediating Tollo signaling in the tracheal epithelium (PubMed:22022271).<ref>PMID:22022271</ref> <ref>PMID:22678360</ref> <ref>PMID:28334607</ref> <ref>PMID:31439792</ref> |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | Axon degeneration is a central pathological feature of many neurodegenerative diseases. Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD(+))-cleaving enzyme whose activation triggers axon destruction. Loss of the biosynthetic enzyme NMNAT2, which converts nicotinamide mononucleotide (NMN) to NAD(+), activates SARM1 via an unknown mechanism. Using structural, biochemical, biophysical, and cellular assays, we demonstrate that SARM1 is activated by an increase in the ratio of NMN to NAD(+) and show that both metabolites compete for binding to the auto-inhibitory N-terminal armadillo repeat (ARM) domain of SARM1. We report structures of the SARM1 ARM domain bound to NMN and of the homo-octameric SARM1 complex in the absence of ligands. We show that NMN influences the structure of SARM1 and demonstrate via mutagenesis that NMN binding is required for injury-induced SARM1 activation and axon destruction. Hence, SARM1 is a metabolic sensor responding to an increased NMN/NAD(+) ratio by cleaving residual NAD(+), thereby inducing feedforward metabolic catastrophe and axonal demise.
| + | |
| | | | |
| - | SARM1 is a metabolic sensor activated by an increased NMN/NAD(+) ratio to trigger axon degeneration.,Figley MD, Gu W, Nanson JD, Shi Y, Sasaki Y, Cunnea K, Malde AK, Jia X, Luo Z, Saikot FK, Mosaiab T, Masic V, Holt S, Hartley-Tassell L, McGuinness HY, Manik MK, Bosanac T, Landsberg MJ, Kerry PS, Mobli M, Hughes RO, Milbrandt J, Kobe B, DiAntonio A, Ve T Neuron. 2021 Mar 1. pii: S0896-6273(21)00083-0. doi:, 10.1016/j.neuron.2021.02.009. PMID:33657413<ref>PMID:33657413</ref>
| + | ==See Also== |
| - | | + | *[[SARM1 3D structures|SARM1 3D structures]] |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 7lcz" style="background-color:#fffaf0;"></div>
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase]] | + | [[Category: Drosophila melanogaster]] |
| - | [[Category: Drome]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Gu, W]] | + | [[Category: Gu W]] |
| - | [[Category: Jia, X]] | + | [[Category: Jia X]] |
| - | [[Category: Kobe, B]] | + | [[Category: Kobe B]] |
| - | [[Category: Luo, Z]] | + | [[Category: Luo Z]] |
| - | [[Category: Manik, M K]] | + | [[Category: Manik MK]] |
| - | [[Category: Nanson, J D]] | + | [[Category: Nanson JD]] |
| - | [[Category: Ve, T]] | + | [[Category: Ve T]] |
| - | [[Category: Allostery]]
| + | |
| - | [[Category: Arm domain]]
| + | |
| - | [[Category: Autoinhibition]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Nadase]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| Structural highlights
Function
SARM1_DROME NAD(+) hydrolase, which plays a key role in axonal degeneration following injury by regulating NAD(+) metabolism (PubMed:22678360, PubMed:28334607). Acts as a negative regulator of MYD88- and TRIF-dependent toll-like receptor signaling pathway by promoting Wallerian degeneration, an injury-induced form of programmed subcellular death which involves degeneration of an axon distal to the injury site (PubMed:22678360). Wallerian degeneration is triggered by NAD(+) depletion: in response to injury, it is activated and catalyzes cleavage of NAD(+) into ADP-D-ribose (ADPR), cyclic ADPR (cADPR) and nicotinamide; NAD(+) cleavage promoting axon destruction (PubMed:22678360, PubMed:28334607, PubMed:31439792). Involved in the down-regulation of the tracheal immune response to Gram-negative bacteria (PubMed:22022271). This is likely by mediating Tollo signaling in the tracheal epithelium (PubMed:22022271).[1] [2] [3] [4]
See Also
References
- ↑ Akhouayri I, Turc C, Royet J, Charroux B. Toll-8/Tollo negatively regulates antimicrobial response in the Drosophila respiratory epithelium. PLoS Pathog. 2011 Oct;7(10):e1002319. doi: 10.1371/journal.ppat.1002319. Epub, 2011 Oct 13. PMID:22022271 doi:http://dx.doi.org/10.1371/journal.ppat.1002319
- ↑ Osterloh JM, Yang J, Rooney TM, Fox AN, Adalbert R, Powell EH, Sheehan AE, Avery MA, Hackett R, Logan MA, MacDonald JM, Ziegenfuss JS, Milde S, Hou YJ, Nathan C, Ding A, Brown RH Jr, Conforti L, Coleman M, Tessier-Lavigne M, Zuchner S, Freeman MR. dSarm/Sarm1 is required for activation of an injury-induced axon death pathway. Science. 2012 Jul 27;337(6093):481-4. doi: 10.1126/science.1223899. Epub 2012 Jun, 7. PMID:22678360 doi:http://dx.doi.org/10.1126/science.1223899
- ↑ Essuman K, Summers DW, Sasaki Y, Mao X, DiAntonio A, Milbrandt J. The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD(+) Cleavage Activity that Promotes Pathological Axonal Degeneration. Neuron. 2017 Mar 22;93(6):1334-1343.e5. doi: 10.1016/j.neuron.2017.02.022. PMID:28334607 doi:http://dx.doi.org/10.1016/j.neuron.2017.02.022
- ↑ 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. NAD(+) cleavage activity by animal and plant TIR domains in cell death pathways. Science. 2019 Aug 23;365(6455):793-799. doi: 10.1126/science.aax1911. PMID:31439792 doi:http://dx.doi.org/10.1126/science.aax1911
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