7lcy

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of the ligand-free ARM domain from Drosophila SARM1

Structural highlights

7lcy is a 3 chain structure with sequence from Drome. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:	Sarm, Ect4, CG43119 (DROME)
Activity:	ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase, with EC number 3.2.2.6
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

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^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ 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. SARM1 is a metabolic sensor activated by an increased NMN/NAD(+) ratio to trigger axon degeneration. Neuron. 2021 Mar 1. pii: S0896-6273(21)00083-0. doi:, 10.1016/j.neuron.2021.02.009. PMID:33657413 doi:http://dx.doi.org/10.1016/j.neuron.2021.02.009

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7lcy"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the ligand-free ARM domain from Drosophila SARM1==
-<StructureSection load='7lcy' size='340' side='right'caption='[[7lcy]]' scene=''>
+<StructureSection load='7lcy' size='340' side='right'caption='[[7lcy]], [[Resolution|resolution]] 3.35&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LCY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LCY FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7lcy]] is a 3 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=7LCY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LCY FirstGlance]. <br>
-</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=7lcy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lcy OCA], [https://pdbe.org/7lcy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lcy RCSB], [https://www.ebi.ac.uk/pdbsum/7lcy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lcy ProSAT]</span></td></tr>
+</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='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=7lcy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lcy OCA], [https://pdbe.org/7lcy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lcy RCSB], [https://www.ebi.ac.uk/pdbsum/7lcy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lcy ProSAT]</span></td></tr>
 </table>
+== 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>
+<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>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 7lcy" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase]]
+[[Category: Drome]]
 [[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 MK]]
+[[Category: Manik, M K]]
-[[Category: McGuinness HY]]
+[[Category: McGuinness, H Y]]
-[[Category: Nanson JD]]
+[[Category: Nanson, J D]]
-[[Category: Ve T]]
+[[Category: Ve, T]]
+[[Category: Allostery]]
+[[Category: Arm domain]]
+[[Category: Autoinhibition]]
+[[Category: Hydrolase]]
+[[Category: Nadase]]
+[[Category: Signaling protein]]

7lcy

From Proteopedia

Current revision

Crystal structure of the ligand-free ARM domain from Drosophila SARM1

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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