7cm7: Difference between revisions
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==NAD+-bound Sarm1 E642A in the self-inhibited state== | ==NAD+-bound Sarm1 E642A in the self-inhibited state== | ||
<StructureSection load='7cm7' size='340' side='right'caption='[[7cm7]]' scene=''> | <StructureSection load='7cm7' size='340' side='right'caption='[[7cm7]], [[Resolution|resolution]] 2.60Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7CM7 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7CM7 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7cm7]] 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=7CM7 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7CM7 FirstGlance]. <br> | ||
</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=7cm7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7cm7 OCA], [http://pdbe.org/7cm7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7cm7 RCSB], [http://www.ebi.ac.uk/pdbsum/7cm7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7cm7 ProSAT]</span></td></tr> | </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='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=7cm7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7cm7 OCA], [http://pdbe.org/7cm7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7cm7 RCSB], [http://www.ebi.ac.uk/pdbsum/7cm7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7cm7 ProSAT]</span></td></tr> | |||
</table> | </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 == | |||
Pathological degeneration of axons disrupts neural circuits and represents one of the hallmarks of neurodegeneration(1-4). Sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 (Sarm1) is a central regulator of this neurodegenerative process(5-8), and its Toll/interleukin-1 receptor (TIR) domain exerts the pro-neurodegenerative action through the NADase activity(9,10). However, the mechanism underlying the stringent control of Sarm1 activation remains to be fully understood. Here, we report the cryo-EM structures of full-length Sarm1 proteins at 2.6- to 3.0-A resolution. We discovered NAD(+) as an unexpected ligand of the armadillo/heat repeat motifs (ARM) domain. This NAD(+) binding facilitated the ARM domain to inhibit the TIR-domain NADase through their domain interface. Disruption of the NAD(+)-binding site or the ARM-TIR interaction caused the constitutively-active Sarm1 leading to axonal degeneration. These findings have suggested the novel NAD(+)-mediated self-inhibition of this central pro-neurodegenerative protein. | |||
The NAD(+)-mediated self-inhibition mechanism of pro-neurodegenerative Sarm1.,Jiang Y, Liu T, Lee CH, Chang Q, Yang J, Zhang Z Nature. 2020 Oct 14. pii: 10.1038/s41586-020-2862-z. doi:, 10.1038/s41586-020-2862-z. PMID:33053563<ref>PMID:33053563</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7cm7" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Jiang Y]] | [[Category: Jiang, Y]] | ||
[[Category: Zhang Z]] | [[Category: Zhang, Z]] | ||
[[Category: Arm]] | |||
[[Category: Hydrolase]] | |||
[[Category: Nadase]] | |||
[[Category: Sam]] | |||
[[Category: Tir]] | |||
Revision as of 10:41, 4 November 2020
NAD+-bound Sarm1 E642A in the self-inhibited stateNAD+-bound Sarm1 E642A in the self-inhibited state
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 PubMedPathological degeneration of axons disrupts neural circuits and represents one of the hallmarks of neurodegeneration(1-4). Sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 (Sarm1) is a central regulator of this neurodegenerative process(5-8), and its Toll/interleukin-1 receptor (TIR) domain exerts the pro-neurodegenerative action through the NADase activity(9,10). However, the mechanism underlying the stringent control of Sarm1 activation remains to be fully understood. Here, we report the cryo-EM structures of full-length Sarm1 proteins at 2.6- to 3.0-A resolution. We discovered NAD(+) as an unexpected ligand of the armadillo/heat repeat motifs (ARM) domain. This NAD(+) binding facilitated the ARM domain to inhibit the TIR-domain NADase through their domain interface. Disruption of the NAD(+)-binding site or the ARM-TIR interaction caused the constitutively-active Sarm1 leading to axonal degeneration. These findings have suggested the novel NAD(+)-mediated self-inhibition of this central pro-neurodegenerative protein. The NAD(+)-mediated self-inhibition mechanism of pro-neurodegenerative Sarm1.,Jiang Y, Liu T, Lee CH, Chang Q, Yang J, Zhang Z Nature. 2020 Oct 14. pii: 10.1038/s41586-020-2862-z. doi:, 10.1038/s41586-020-2862-z. PMID:33053563[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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