View source for 7lcy


==Crystal structure of the ligand-free ARM domain from Drosophila SARM1==
<StructureSection load='7lcy' size='340' side='right'caption='[[7lcy]], [[Resolution|resolution]] 3.35&Aring;' scene=''>
== Structural highlights ==
<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='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: Jia, X]]
[[Category: Kobe, B]]
[[Category: Luo, Z]]
[[Category: Manik, M K]]
[[Category: McGuinness, H Y]]
[[Category: Nanson, J D]]
[[Category: Ve, T]]
[[Category: Allostery]]
[[Category: Arm domain]]
[[Category: Autoinhibition]]
[[Category: Hydrolase]]
[[Category: Nadase]]
[[Category: Signaling protein]]