View source for 6zg0


==SARM1 SAM1-2 domains==
<StructureSection load='6zg0' size='340' side='right'caption='[[6zg0]], [[Resolution|resolution]] 7.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6zg0]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZG0 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZG0 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SARM1, KIAA0524, SAMD2, SARM ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6zg0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zg0 OCA], [http://pdbe.org/6zg0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6zg0 RCSB], [http://www.ebi.ac.uk/pdbsum/6zg0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6zg0 ProSAT]</span></td></tr>
</table>
== Function ==
[[http://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>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
SARM1 an executor of axonal degeneration, displays NADase activity that depletes the key cellular metabolite, NAD+, in response to nerve injury. The basis of SARM1 inhibition, and its activation under stress conditions are still unknown. Here, we present cryo-EM maps of SARM1 at 2.9 and 2.7 A resolution. These indicate that SARM1 homo-octamer avoids premature activation by assuming a packed conformation, with ordered inner and peripheral rings, that prevents dimerization and activation of the catalytic domains. This inactive conformation is stabilized by binding of SARM1's own substrate NAD+ in an allosteric location, away from the catalytic sites. This model was validated by mutagenesis of the allosteric site, which led to constitutively active SARM1. We propose that the reduction of cellular NAD+ concentration contributes to the disassembly of SARM1's peripheral ring, which allows formation of active NADase domain dimers, thereby further depleting NAD+ to cause an energetic catastrophe and cell death.

The structural basis for SARM1 inhibition and activation under energetic stress.,Sporny M, Guez-Haddad J, Khazma T, Yaron A, Dessau M, Shkolnisky Y, Mim C, Isupov MN, Zalk R, Hons M, Opatowsky Y Elife. 2020 Nov 13;9. pii: 62021. doi: 10.7554/eLife.62021. PMID:33185189<ref>PMID:33185189</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6zg0" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Dessau, M]]
[[Category: Guez-Haddad, J]]
[[Category: Hons, M]]
[[Category: Isupov, M N]]
[[Category: Khazma, T]]
[[Category: Mim, C]]
[[Category: Opatowsky, Y]]
[[Category: Sporny, M]]
[[Category: Yaron, A]]
[[Category: Zalk, R]]
[[Category: Hydrolase]]
[[Category: Nadase]]
[[Category: Sam domain]]