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| | <StructureSection load='6zfx' size='340' side='right'caption='[[6zfx]], [[Resolution|resolution]] 2.88Å' scene=''> | | <StructureSection load='6zfx' size='340' side='right'caption='[[6zfx]], [[Resolution|resolution]] 2.88Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6zfx]] 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=6ZFX OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZFX FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6zfx]] is a 8 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=6ZFX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZFX FirstGlance]. <br> |
| | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=S1N:(~{E})-4-methylnon-4-enedial'>S1N</scene></td></tr> | | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=S1N:(~{E})-4-methylnon-4-enedial'>S1N</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'>[https://proteopedia.org/fgij/fg.htm?mol=6zfx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zfx OCA], [https://pdbe.org/6zfx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zfx RCSB], [https://www.ebi.ac.uk/pdbsum/6zfx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zfx ProSAT]</span></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=6zfx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zfx OCA], [http://pdbe.org/6zfx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6zfx RCSB], [http://www.ebi.ac.uk/pdbsum/6zfx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6zfx ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == 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> | + | [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> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6zfx" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6zfx" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[SARM1 3D structures|SARM1 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Dessau, M]] | + | [[Category: Dessau M]] |
| - | [[Category: Guez-Haddad, J]] | + | [[Category: Guez-Haddad J]] |
| - | [[Category: Hons, M]] | + | [[Category: Hons M]] |
| - | [[Category: Isupov, M N]] | + | [[Category: Isupov MN]] |
| - | [[Category: Khazma, T]] | + | [[Category: Khazma T]] |
| - | [[Category: Mim, C]] | + | [[Category: Mim C]] |
| - | [[Category: Opatowsky, Y]] | + | [[Category: Opatowsky Y]] |
| - | [[Category: Sporny, M]] | + | [[Category: Sporny M]] |
| - | [[Category: Yaron, A]] | + | [[Category: Yaron A]] |
| - | [[Category: Zalk, R]] | + | [[Category: Zalk R]] |
| - | [[Category: Arm domain]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Nadase]]
| + | |
| - | [[Category: Sam domain]]
| + | |
| - | [[Category: Tir domain]]
| + | |
| Structural highlights
Function
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.[1] [2] [3] [4]
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[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Liberati NT, Fitzgerald KA, Kim DH, Feinbaum R, Golenbock DT, Ausubel FM. Requirement for a conserved Toll/interleukin-1 resistance domain protein in the Caenorhabditis elegans immune response. Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6593-8. PMID:15123841 doi:http://dx.doi.org/10.1073/pnas.0308625101
- ↑ Carty M, Goodbody R, Schroder M, Stack J, Moynagh PN, Bowie AG. The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nat Immunol. 2006 Oct;7(10):1074-81. doi: 10.1038/ni1382. Epub 2006 Sep 10. PMID:16964262 doi:http://dx.doi.org/10.1038/ni1382
- ↑ O'Neill LA. DisSARMing Toll-like receptor signaling. Nat Immunol. 2006 Oct;7(10):1023-5. doi: 10.1038/ni1006-1023. PMID:16985498 doi:http://dx.doi.org/10.1038/ni1006-1023
- ↑ Peng J, Yuan Q, Lin B, Panneerselvam P, Wang X, Luan XL, Lim SK, Leung BP, Ho B, Ding JL. SARM inhibits both TRIF- and MyD88-mediated AP-1 activation. Eur J Immunol. 2010 Jun;40(6):1738-47. doi: 10.1002/eji.200940034. PMID:20306472 doi:http://dx.doi.org/10.1002/eji.200940034
- ↑ Sporny M, Guez-Haddad J, Khazma T, Yaron A, Dessau M, Shkolnisky Y, Mim C, Isupov MN, Zalk R, Hons M, Opatowsky Y. The structural basis for SARM1 inhibition and activation under energetic stress. Elife. 2020 Nov 13;9. pii: 62021. doi: 10.7554/eLife.62021. PMID:33185189 doi:http://dx.doi.org/10.7554/eLife.62021
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