UniProt ID: F1QWA8 |
FUNCTION: NAD(+) hydrolase, which plays a key role in axonal degeneration following injury by regulating NAD(+) metabolism (PubMed:32001778). Acts as a negative regulator of MYD88- and TRIF- dependent toll-like receptor signaling pathway by promoting Wallerian degeneration, an injury-induced form of programmed subcellular death which involves degeneration of an axon distal to the injury site (By similarity). Wallerian degeneration is triggerred by NAD(+) depletion: in response to injury, SARM1 is activated and catalyzes cleavage of NAD(+) into ADP-D-ribose (ADPR), cyclic ADPR (cADPR) and nicotinamide; NAD(+) cleavage promoting cytoskeletal degradation and axon destruction (PubMed:28334607). Also able to hydrolyze NADP(+), but not other NAD(+)-related molecules (By similarity). Can activate neuronal cell death in response to stress (By similarity). {ECO:0000250|UniProtKB:Q6SZW1, ECO:0000269|PubMed:28334607, ECO:0000269|PubMed:32001778}. CATALYTIC ACTIVITY: Reaction=H2O + NAD(+) = ADP-D-ribose + H(+) + nicotinamide; Xref=Rhea:RHEA:16301, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:17154, ChEBI:CHEBI:57540, ChEBI:CHEBI:57967; EC=3.2.2.6; Evidence={ECO:0000269|PubMed:28334607}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16302; Evidence={ECO:0000269|PubMed:28334607}; CATALYTIC ACTIVITY: Reaction=NAD(+) = cyclic ADP-beta-D-ribose + H(+) + nicotinamide; Xref=Rhea:RHEA:38611, ChEBI:CHEBI:15378, ChEBI:CHEBI:17154, ChEBI:CHEBI:57540, ChEBI:CHEBI:73672; Evidence={ECO:0000250|UniProtKB:Q6SZW1}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38612; Evidence={ECO:0000250|UniProtKB:Q6SZW1}; CATALYTIC ACTIVITY: Reaction=H2O + NADP(+) = ADP-D-ribose 2'-phosphate + H(+) + nicotinamide; Xref=Rhea:RHEA:19849, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:17154, ChEBI:CHEBI:58349, ChEBI:CHEBI:58673; Evidence={ECO:0000250|UniProtKB:Q6SZW1}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19850; Evidence={ECO:0000250|UniProtKB:Q6SZW1}; ACTIVITY REGULATION: Autoinhibited: in the inactive state, the enzymatic TIR domain is held apart by the autoinhibiting ARM repeats. NAD(+)-binding to ARM repeats maintains an inactive state by promoting interaction between ARM repeats and the TIR domain, thereby facilitating inhibition of the enzymatic TIR domain. Following activation, possibly by nicotinamide mononucleotide (NMN), auto- inhibitory interactions are released, allowing self-association of the TIR domains and subsequent activation of the NAD(+) hydrolase (NADase) activity. Self-association of TIR domains is facilitated by the octamer of SAM domains. {ECO:0000250|UniProtKB:Q6SZW1}. SUBUNIT: Homooctamer; forms an octameric ring via SAM domains. {ECO:0000250|UniProtKB:Q6SZW1}. SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q6SZW1}. Cell projection, axon {ECO:0000250|UniProtKB:Q6PDS3}. Cell projection, dendrite {ECO:0000250|UniProtKB:Q6PDS3}. Synapse {ECO:0000250|UniProtKB:Q6PDS3}. Mitochondrion {ECO:0000250|UniProtKB:Q6SZW1}. Note=Associated with microtubules. {ECO:0000250|UniProtKB:Q6PDS3}. DOMAIN: The TIR domain mediates NAD(+) hydrolase (NADase) activity. Self-association of TIR domains is required for NADase activity. {ECO:0000250|UniProtKB:Q6SZW1}. DOMAIN: The ARM repeats inhibit the NAD(+) hydrolase (NADase) activity by binding to NAD(+): NAD(+)-binding to ARM repeats facilitates inhibition of the TIR domain NADase through their domain interface. In contrast to classical ARM repeats, the last helix of ARM 6 does not fold back to interact with the first two helices, but instead turns towards the N-terminus of SARM1. As a result, the two following motifs ARM 7 and ARM 8 reverse their directions and lie perpendicularly. Moreover, ARM repeats interact with different domains not only within each protomer but also of the adjacent ones. {ECO:0000250|UniProtKB:Q6SZW1}. DISRUPTION PHENOTYPE: Absence of sarm1 provides a level of protection against axon degeneration (PubMed:32001778). Schwann cells are protected from chemotoxicity by delaying axon degeneration (PubMed:32001778). Absence of Sarm1 does not promote axon resealing (PubMed:32728661). {ECO:0000269|PubMed:32001778, ECO:0000269|PubMed:32728661}. SIMILARITY: Belongs to the SARM1 family. {ECO:0000305}. |
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