SARM1: Difference between revisions

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Michal Harel, Alexander Berchansky

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+<StructureSection load='7cm6' size='340' side='right' caption='Human SARM1 complex with NAD(+) (PDB ID [[7cm6]]).' scene='91/918463/Cv/1'>
-<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''>
 == Function ==
-'''SARM1''' or '''NAD(+) hydrolase''' or '''sterile alpha and TIR motif-containing protein 1''' or '''NADase''' is a NAD-cleaving enzyme whose activation triggers axon destruction.  SARM1 is a metabolic sensor responding to an increased NMN/NAD+ ratio by cleaving residual NAD+ and inducing axonal demise<ref>PMID:33657413</ref>.
+'''SARM1''' or '''NAD(+) hydrolase''' or '''sterile alpha and TIR motif-containing protein 1''' or '''NADase''' is a NAD-cleaving enzyme<ref>PMID:28334607</ref> whose activation triggers Wallerian axon destruction after injury<ref>PMID:22678360</ref>. SARM1 is thought to be a metabolic sensor responding to an increased NMN/NAD+ ratio by cleaving residual NAD+ and inducing axonal demise<ref>PMID:33657413</ref>. SARM1-induced axon destruction can be counteracted by increased NAD+ synthesis<ref>PMID:25908823</ref>.
 == Disease ==
-== Relevance ==
+SARM1 mutations were found in ALS patients<ref>PMID:34796871</ref>.  SARM1 induces axonal degeneration after nerve injury<ref>PMID:23946415</ref> and in other neuropathological conditions, such as chemotherapy induced peripheral neuropathy (CIPN), a dose-restricting chemotherapy side effect<ref>PMID:27797810</ref>,<ref>PMID:33318563</ref>. Consistent with its pro-degenerative function, genetic ablation of SARM1 protects against axonal and other types of neuronal degeneration, without inflicting any apparent impediments on the animal models<ref>PMID:30842236</ref>. Particularly, it was demonstrated that SARM1 ablation provides protection against CIPN induced by the widely used chemotherapy agents vincristine<ref>PMID:31484833</ref>, cisplatin and paclitaxel<ref>PMID:33964142</ref>.
 == Structural highlights ==
-This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.
+The 3D structure of SARM1 shows the <scene name='91/918463/Cv/2'>octamer structure</scene> with outer ring dimension of 200A, inner ring of 45A and thickness of 60A<ref>PMID:33053563</ref>. The 3 domains of SARM1 are <scene name='91/918463/Cv/3'>ARM, SAM and TIR</scene>. The <scene name='91/918463/Cv/4'>interaction of the ARM and TIR domains cause</scene> the autoinhibition of SARM1. <scene name='91/918463/Cv1/1'>NAD(+) binding pocket is at the concave side</scene> of the ARM domain. <scene name='91/918463/Cv1/3'>NAD(+)/protein interactions</scene>.  The domain topology includes an N-terminal ARM domain, followed by two SAM and one TIR domain. NADase activity requires homo-oligomerization of TIR domains<ref>PMID:35334231</ref>, which is naturally facilitated by the SAM domains through complementing electrostatic and hydrophobic interactions that assembles eight protomers into a closed ring structure<ref>PMID:31278906</ref>,<ref>PMID:31439792</ref>. The ARM domain inhibits NADase activity in cultured cells and in axons<ref>PMID:27671644</ref>. In the auto-inhibitory conformation, a tightly packed arrangement of overlapping ARM domains surrounds the SAM core ring and supports TIR docking in a way that keeps them separated from each other to prevent their oligomerization and NADase activity. Accordingly, SARM1 activation involves a conformational re-arrangement that would allow nearing of the TIR domains, as demonstrated by the introduction of NMN or by gain-of-function point mutations that disturb ARM-TIR interactions<ref>PMID:33185189</ref>,<ref>PMID:32755591</ref>,<ref>PMID:33468661</ref>,<ref>PMID:33053563</ref>.
+==3D structures of SARM1==
+[[SARM1 3D structures]]
 </StructureSection>
 == References ==
 <references/>
+This page was mainly constructed by Yarden Opatowsky.
+[[Category:Topic Page]]