SARM1
Domain
The TIR domain mediates NAD(+) hydrolase (NADase) activity (PubMed:28334607). Self-association of TIR domains is required for NADase activity (PubMed:27671644, PubMed:31278906).
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 (PubMed:33053563). 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 (PubMed:33053563). As a result, the two following motifs ARM 7 and ARM 8 reverse their directions and lie perpendicularly (PubMed:33053563). Moreover, ARM repeats interact with different domains not only within each protomer but also of the adjacent ones (PubMed:33053563).
Function
NAD(+) hydrolase, which plays a key role in axonal degeneration following injury by regulating NAD(+) metabolism (PubMed:25908823, PubMed:27671644, PubMed:28334607). 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 (PubMed:15123841, PubMed:16964262, PubMed:20306472, PubMed:25908823). Wallerian degeneration is triggered 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:25908823, PubMed:28334607, PubMed:30333228, PubMed:31128467, PubMed:31439792, PubMed:31439793, PubMed:32049506, PubMed:32828421, PubMed:33053563). Also able to hydrolyze NADP(+), but not other NAD(+)-related molecules (PubMed:29395922). Can activate neuronal cell death in response to stress (PubMed:20306472). Regulates dendritic arborization through the MAPK4-JNK pathway (By similarity). 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 (PubMed:16964262).
Post-translational modifications
Phosphorylation at Ser-548 by JNK kinases (MAPK8, MAPK9 and /or MAPK10) enhance the NAD(+) hydrolase (NADase) activity (PubMed:30333228). Phosphorylation at Ser-548 and subsequent activation takes place in response to oxidative stress conditions and inhibits mitochondrial respiration (PubMed:30333228).
Sequence Similarities
Belongs to the SARM1 family.
Tissue Specificity
Predominantly expressed in brain, kidney and liver. Expressed at lower level in placenta.
Cellular localization
- Cytoplasm
- Cell projection
- Axon
- Cell projection
- Dendrite
- Synapse
- Mitochondrion
- Associated with microtubules.
Alternative names
KIAA0524, SAMD2, SARM, SARM1, NAD(+) hydrolase SARM1, NADase SARM1, hSARM1, NADP(+) hydrolase SARM1, Sterile alpha and Armadillo repeat protein, Sterile alpha and TIR motif-containing protein 1, Sterile alpha motif domain-containing protein 2, Tir-1 homolog, MyD88-5, SAM domain-containing protein 2, HsTIR