View source for 8p2l


==A CHIMERA construct containing human SARM1 ARM and SAM domains and C. elegans TIR domain.==
<StructureSection load='8p2l' size='340' side='right'caption='[[8p2l]], [[Resolution|resolution]] 2.68&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8p2l]] is a 16 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8P2L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8P2L FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.68&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene></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=8p2l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8p2l OCA], [https://pdbe.org/8p2l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8p2l RCSB], [https://www.ebi.ac.uk/pdbsum/8p2l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8p2l ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/SARM1_HUMAN SARM1_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.<ref>PMID:15123841</ref> <ref>PMID:16964262</ref> <ref>PMID:16985498</ref> <ref>PMID:20306472</ref> [https://www.uniprot.org/uniprot/SARM1_CAEEL SARM1_CAEEL] NAD(+) hydrolase, which plays a key role in non-apoptotic cell death by regulating NAD(+) metabolism (PubMed:27671644). In response to stress, homooligomerizes and catalyzes cleavage of NAD(+) into ADP-D-ribose (ADPR) and nicotinamide; NAD(+) cleavage promoting non-apoptotic neuronal cell death (PubMed:31439792). In males, involved in non-apoptotic death of the linker cell which guides gonad elongation during larval development (PubMed:22363008). Required for both innate immune response and specification of AWC(OFF) neuron (PubMed:15048112, PubMed:15123841, PubMed:15625192). During late embryogenesis, it acts downstream of CAMKII (unc-43) to regulate specification of asymmetric odorant receptors in AWC(OFF) neuron via the nsy-1/ASK1 pmk-1/p38 MAP kinase signaling cascade. Required to localize nsy-1 to postsynaptic regions of AWC neuron, suggesting that it may act by assembling a signaling complex that regulate odorant receptor expression (PubMed:15625192). Also plays a central role in resistance to infection to a broad range of bacterial and fungi pathogens, possibly by activating pmk-1, independently of the NF-kappa-B pathway. Required for expression of antimicrobial peptides nlp-29 and nlp-31 (PubMed:15048112, PubMed:15123841). Its role in immune response and neuron specification may be mediated by the same nsy-1/ASK1 pmk-1/p38 MAP kinase cascade signaling pathway (PubMed:15048112, PubMed:15123841, PubMed:15625192). Involved in the response to anoxic conditions probably by activating the p38 pathway composed of nsy-1/sek-1/pmk-1 (PubMed:21212236). Involved in regulation of the serotonergic response of ADF neurons to pathogenic food (PubMed:23505381). In addition, plays a role in the up-regulation of gcs-1 upon arsenite treatment, most likely through activation of pmk-1, to confer protection against toxicity induced by heavy metals (PubMed:25204677).<ref>PMID:15048112</ref> <ref>PMID:15123841</ref> <ref>PMID:15625192</ref> <ref>PMID:21212236</ref> <ref>PMID:22363008</ref> <ref>PMID:23505381</ref> <ref>PMID:25204677</ref> <ref>PMID:27671644</ref> <ref>PMID:31439792</ref>   Regulates expression of antimicrobial peptide nlp-29 in response to fungal infection or physical injury.<ref>PMID:18394898</ref> 
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== Publication Abstract from PubMed ==
Wallerian axonal degeneration (WD) does not occur in the nematode C. elegans, in contrast to other model animals. However, WD depends on the NADase activity of SARM1, a protein that is also expressed in C. elegans (ceSARM/ceTIR-1). We hypothesized that differences in SARM between species might exist and account for the divergence in WD. We first show that expression of the human (h)SARM1, but not ceTIR-1, in C. elegans neurons is sufficient to confer axon degeneration after nerve injury. Next, we determined the cryoelectron microscopy structure of ceTIR-1 and found that, unlike hSARM1, which exists as an auto-inhibited ring octamer, ceTIR-1 forms a readily active 9-mer. Enzymatically, the NADase activity of ceTIR-1 is substantially weaker (10-fold higher Km) than that of hSARM1, and even when fully active, it falls short of consuming all cellular NAD(+). Our experiments provide insight into the molecular mechanisms and evolution of SARM orthologs and WD across species.

Structure-function analysis of ceTIR-1/hSARM1 explains the lack of Wallerian axonal degeneration in C. elegans.,Khazma T, Grossman A, Guez-Haddad J, Feng C, Dabas H, Sain R, Weitman M, Zalk R, Isupov MN, Hammarlund M, Hons M, Opatowsky Y Cell Rep. 2023 Aug 26;42(9):113026. doi: 10.1016/j.celrep.2023.113026. PMID:37635352<ref>PMID:37635352</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 8p2l" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Isupov MN]]
[[Category: Opatowsky Y]]