SARM1
entrez
23098
canonical
uniprot
Q6SZW1
canonical
ensembl
ENSG00000004139
resolver
ensp
ENSP00000468032
resolver
genesymbol
SARM1
resolver
genesymbol_syn
KIAA0524
resolver
genesymbol_syn
SAMD2
resolver
genesymbol_syn
SARM
resolver
hgnc
HGNC:17074
resolver
uniprot
O60277
resolver
uniprot
Q05B42
resolver
uniprot
Q0D2N8
resolver
uniprot
Q7LGG3
resolver
uniprot
Q9NXY5
resolver
uniprot_entry
Q05B42_HUMAN
resolver
uniprot_entry
Q0D2N8_HUMAN
resolver
uniprot_entry
SARM1_HUMAN
resolver
uniprot_sec
O60277
resolver
uniprot_sec
Q7LGG3
resolver
uniprot_sec
Q9NXY5
resolver
activity_regulation
ACTIVITY REGULATION: Autoinhibited: in the inactive state, the enzymatic TIR domain is held apart by the autoinhibiting ARM repeats (PubMed:27671644, PubMed:31278906, PubMed:32755591, PubMed:33053563). 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 (PubMed:33053563). 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 (PubMed:27671644, PubMed:31128467, PubMed:32755591). Self-association of TIR domains is facilitated by the octamer of SAM domains (PubMed:31278906, PubMed:31439792). NAD(+) hydrolase activity is inhibited by nicotinamide (PubMed:28334607). Specifically inhibited by berberine chloride and zinc chloride (PubMed:32828421). {ECO:0000269|PubMed:27671644, ECO:0000269|PubMed:28334607, ECO:0000269|PubMed:31128467, ECO:0000269|PubMed:31278906, ECO:0000269|PubMed:31439792, ECO:0000269|PubMed:32755591, ECO:0000269|PubMed:32828421, ECO:0000269|PubMed:33053563}.
uniprot
proteins
amino_acid_sequence
MVLTLLLSAYKLCRFFAMSGPRPGAERLAVPGPDGGGGTGPWWAAGGRGPREVSPGAGTEVQDALERALPELQQALSALKQAGGARAVGAGLAEVFQLVEEAWLLPAVGREVAQGLCDAIRLDGGLDLLLRLLQAPELETRVQAARLLEQILVAENRDRVARIGLGVILNLAKEREPVELARSVAGILEHMFKHSEETCQRLVAAGGLDAVLYWCRRTDPALLRHCALALGNCALHGGQAVQRRMVEKRAAEWLFPLAFSKEDELLRLHACLAVAVLATNKEVEREVERSGTLALVEPLVASLDPGRFARCLVDASDTSQGRGPDDLQRLVPLLDSNRLEAQCIGAFYLCAEAAIKSLQGKTKVFSDIGAIQSLKRLVSYSTNGTKSALAKRALRLLGEEVPRPILPSVPSWKEAEVQTWLQQIGFSKYCESFREQQVDGDLLLRLTEEELQTDLGMKSGITRKRFFRELTELKTFANYSTCDRSNLADWLGSLDPRFRQYTYGLVSCGLDRSLLHRVSEQQLLEDCGIHLGVHRARILTAAREMLHSPLPCTGGKPSGDTPDVFISYRRNSGSQLASLLKVHLQLHGFSVFIDVEKLEAGKFEDKLIQSVMGARNFVLVLSPGALDKCMQDHDCKDWVHKEIVTALSCGKNIVPIIDGFEWPEPQVLPEDMQAVLTFNGIKWSHEYQEATIEKIIRFLQGRSSRDSSAGSDTSLEGAAPMGPT
uniprot
proteins
ec_number
3.2.2.-
uniprot
proteins
ec_number
3.2.2.6
uniprot
proteins
function
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). Acts as a non-self dsDNA sensor in a sequence-independent manner to elicit NAD(+) degradation and thus to promote programmed cell death (PubMed:41138726). {ECO:0000250|UniProtKB:Q6PDS3, ECO:0000269|PubMed:15123841, ECO:0000269|PubMed:16964262, ECO:0000269|PubMed:20306472, ECO:0000269|PubMed:25908823, ECO:0000269|PubMed:27671644, ECO:0000269|PubMed:28334607, ECO:0000269|PubMed:29395922, ECO:0000269|PubMed:30333228, ECO:0000269|PubMed:31128467, ECO:0000269|PubMed:31439792, ECO:0000269|PubMed:31439793, ECO:0000269|PubMed:32049506, ECO:0000269|PubMed:32828421, ECO:0000269|PubMed:33053563, ECO:0000269|PubMed:41138726}.
uniprot
proteins
mass_dalton
79388
uniprot
proteins
mutagenesis
MUTAGEN 11; /note="K->A: No effect on mitochondrial localization."; /evidence="ECO:0000269|PubMed:22145856"; MUTAGEN 14; /note="R->A: Loss in ability to localize to mitochondria and reduction in apoptotic activity."; /evidence="ECO:0000269|PubMed:22145856"; MUTAGEN 22; /note="R->A: No effect on mitochondrial localization."; /evidence="ECO:0000269|PubMed:22145856"; MUTAGEN 27; /note="R->A: No effect on mitochondrial localization."; /evidence="ECO:0000269|PubMed:22145856"; MUTAGEN 103; /note="W->A: In WQH to A mutant: Increased NAD(+)-binding to ARM repeats, leading to decreased NAD(+) hydrolase activity; when associated with A-150 and A-190."; /evidence="ECO:0000269|PubMed:33053563"; MUTAGEN 110; /note="R->A: In RRK to A mutant: Slightly reduced NAD(+)-binding to ARM repeats; when associated with A-157 and A-193."; /evidence="ECO:0000269|PubMed:33053563"; MUTAGEN 110; /note="R->E: In RRK to E mutant: Strongly reduced NAD(+)-binding to ARM repeats, leading to enhanced NAD(+) hydrolase activity and constitutive axonal degeneration in absence of injury; when associated with E-157 and A-193."; /evidence="ECO:0000269|PubMed:33053563"; MUTAGEN 150; /note="Q->A: In WQH to A mutant: Increased NAD(+)-binding to ARM repeats, leading to decreased NAD(+) hydrolase activity; when associated with A-103 and A-190."; /evidence="ECO:0000269|PubMed:33053563"; MUTAGEN 157; /note="R->A: In RRK to A mutant: Slightly reduced NAD(+)-binding to ARM repeats; when associated with A-110 and A-193."; /evidence="ECO:0000269|PubMed:33053563"; MUTAGEN 157; /note="R->E: In RRK to E mutant: Strongly reduced NAD(+)-binding to ARM repeats, leading to enhanced NAD(+) hydrolase activity and constitutive axonal degeneration in absence of injury; when associated with E-110 and A-193."; /evidence="ECO:0000269|PubMed:33053563"; MUTAGEN 190; /note="H->A: In WQH to A mutant: Increased NAD(+)-binding to ARM repeats, leading to decreased NAD(+) hydrolase activity; when associated with A-103 and A-150."; /evidence="ECO:0000269|PubMed:33053563"; MUTAGEN 193; /note="K->A: In RRK to A mutant: Slightly reduced NAD(+)-binding to ARM repeats; when associated with A-110 and A-157."; /evidence="ECO:0000269|PubMed:33053563"; MUTAGEN 193; /note="K->E: In RRK to E mutant: Strongly reduced NAD(+)-binding to ARM repeats, leading to enhanced NAD(+) hydrolase activity and constitutive axonal degeneration in absence of injury; when associated with E-110 and E-157."; /evidence="ECO:0000269|PubMed:33053563"; MUTAGEN 249; /note="R->A: No effect on octamer formation; does not affect NAD(+) hydrolase activity."; /evidence="ECO:0000269|PubMed:33053563"; MUTAGEN 253; /note="W->A: Constitutively active mutant; strong ability to trigger axonal degeneration caused by disrupted interaction between the TIR domain and ARM repeats."; /evidence="ECO:0000269|PubMed:33053563"; MUTAGEN 259; /note="F->A: No effect on octamer formation. Shows increased NAD(+) hydrolase activity and ability to trigger axonal degeneration."; /evidence="ECO:0000269|PubMed:33053563"; MUTAGEN 261; /note="K->A: No effect on octamer formation; does not affect NAD(+) hydrolase activity."; /evidence="ECO:0000269|PubMed:33053563"; MUTAGEN 408; /note="S->A: Does not affect phosphorylation level."; /evidence="ECO:0000269|PubMed:30333228"; MUTAGEN 411; /note="S->A: Does not affect phosphorylation level."; /evidence="ECO:0000269|PubMed:30333228"; MUTAGEN 419; /note="T->A: Does not affect phosphorylation level."; /evidence="ECO:0000269|PubMed:30333228"; MUTAGEN 427; /note="S->A: Does not affect phosphorylation level."; /evidence="ECO:0000269|PubMed:30333228"; MUTAGEN 432; /note="S->A: Does not affect phosphorylation level."; /evidence="ECO:0000269|PubMed:30333228"; MUTAGEN 447; /note="T->A: Does not affect phosphorylation level."; /evidence="ECO:0000269|PubMed:30333228"; MUTAGEN 453; /note="T->A: Does not affect phosphorylation level."; /evidence="ECO:0000269|PubMed:30333228"; MUTAGEN 454; /note="D->K: Reduced ability to form an octameric ring and promote axonal degeneration following injury."; /evidence="ECO:0000269|PubMed:31278906"; MUTAGEN 461..464; /note="ITRK->DTRD: Strongly reduced ability to form an octameric ring and promote axonal degeneration following injury."; /evidence="ECO:0000269|PubMed:31278906"; MUTAGEN 461; /note="I->D: Reduced ability to form an octameric ring and promote axonal degeneration following injury."; /evidence="ECO:0000269|PubMed:31278906"; MUTAGEN 462; /note="T->A: Does not affect phosphorylation level."; /evidence="ECO:0000269|PubMed:30333228"; MUTAGEN 464; /note="K->D: Reduced ability to form an octameric ring and promote axonal degeneration following injury."; /evidence="ECO:0000269|PubMed:31278906"; MUTAGEN 471; /note="T->A: Does not affect phosphorylation level."; /evidence="ECO:0000269|PubMed:30333228"; MUTAGEN 475; /note="T->A: Does not affect phosphorylation level."; /evidence="ECO:0000269|PubMed:30333228"; MUTAGEN 480; /note="S->A: Does not affect phosphorylation level."; /evidence="ECO:0000269|PubMed:30333228"; MUTAGEN 481; /note="T->A: Does not affect phosphorylation level."; /evidence="ECO:0000269|PubMed:30333228"; MUTAGEN 485; /note="S->A: Does not affect phosphorylation level."; /evidence="ECO:0000269|PubMed:30333228"; MUTAGEN 493; /note="S->A: Does not affect phosphorylation level."; /evidence="ECO:0000269|PubMed:30333228"; MUTAGEN 502; /note="T->A: Does not affect phosphorylation level."; /evidence="ECO:0000269|PubMed:30333228"; MUTAGEN 507; /note="S->A: Does not affect phosphorylation level."; /evidence="ECO:0000269|PubMed:30333228"; MUTAGEN 513; /note="S->A: Does not affect phosphorylation level."; /evidence="ECO:0000269|PubMed:30333228"; MUTAGEN 519; /note="S->A: Does not affect phosphorylation level."; /evidence="ECO:0000269|PubMed:30333228"; MUTAGEN 531..533; /note="LGV->DGD: Slightly reduced ability to form an octameric ring and promote axonal degeneration following injury."; /evidence="ECO:0000269|PubMed:31278906"; MUTAGEN 531; /note="L->D: Slightly reduced ability to form an octameric ring and promote axonal degeneration following injury."; /evidence="ECO:0000269|PubMed:31278906"; MUTAGEN 533; /note="V->D: Slightly reduced ability to form an octameric ring and promote axonal degeneration following injury."; /evidence="ECO:0000269|PubMed:31278906"; MUTAGEN 540; /note="T->A: Does not affect phosphorylation level."; /evidence="ECO:0000269|PubMed:30333228"; MUTAGEN 548; /note="S->A: Decreased phosphorylation, leading to reduced NAD(+) hydrolase activity."; /evidence="ECO:0000269|PubMed:30333228"; MUTAGEN 568; /note="Y->A: Loss of NAD(+) hydrolase activity."; /evidence="ECO:0000269|PubMed:31439792"; MUTAGEN 569..570; /note="RR->AA: Loss of NAD(+) hydrolase activity."; /evidence="ECO:0000269|PubMed:31439792"; MUTAGEN 569; /note="R->A: Loss of NAD(+) hydrolase activity."; /evidence="ECO:0000269|PubMed:31439792"; MUTAGEN 579; /note="L->A: Reduced NAD(+) hydrolase activity."; /evidence="ECO:0000269|PubMed:31439792"; MUTAGEN 594; /note="D->A: Reduced NAD(+) hydrolase activity."; /evidence="ECO:0000269|PubMed:31439792"; MUTAGEN 596; /note="E->K: Loss of NAD(+) hydrolase activity. Abolished ability to promote axonal degeneration following injury."; /evidence="ECO:0000269|PubMed:27671644, ECO:0000269|PubMed:28334607, ECO:0000269|PubMed:31439792"; MUTAGEN 597; /note="K->E: Dominant negative mutant that blocks axon degeneration after axotomy."; /evidence="ECO:0000269|PubMed:27671644"; MUTAGEN 601; /note="G->P: Loss of NAD(+) hydrolase activity. Abolished ability to promote axonal degeneration following injury."; /evidence="ECO:0000269|PubMed:27671644, ECO:0000269|PubMed:28334607, ECO:0000269|PubMed:31439792"; MUTAGEN 602; /note="K->E: Complete loss of dsDNA binding; when associated with E-628 and E-636."; /evidence="ECO:0000269|PubMed:41138726"; MUTAGEN 604; /note="E->K: Does not affect ability to promote axonal degeneration following injury."; /evidence="ECO:0000269|PubMed:27671644"; MUTAGEN 626; /note="L->M: Does not affect ability to promote axonal degeneration following injury."; /evidence="ECO:0000269|PubMed:27671644"; MUTAGEN 627; /note="D->K: Abolished ability to promote axonal degeneration following injury."; /evidence="ECO:0000269|PubMed:27671644"; MUTAGEN 628; /note="K->D: Abolished ability to promote axonal degeneration following injury."; /evidence="ECO:0000269|PubMed:27671644"; MUTAGEN 628; /note="K->E: Complete loss of dsDNA binding; when associated with E-602 and E-636."; /evidence="ECO:0000269|PubMed:41138726"; MUTAGEN 629; /note="C->A: Abolished NAD(+) hydrolase activity."; /evidence="ECO:0000269|PubMed:32828421"; MUTAGEN 629; /note="C->S: Abolished ability to promote axonal degeneration following injury."; /evidence="ECO:0000269|PubMed:27671644"; MUTAGEN 632; /note="D->K: Does not affect ability to promote axonal degeneration following injury."; /evidence="ECO:0000269|PubMed:27671644"; MUTAGEN 635; /note="C->A: Abolished NAD(+) hydrolase activity."; /evidence="ECO:0000269|PubMed:32828421"; MUTAGEN 636; /note="K->E: Complete loss of dsDNA binding; when associated with E-602 and E-628."; /evidence="ECO:0000269|PubMed:41138726"; MUTAGEN 642; /note="E->A: Abolished NAD(+) hydrolase activity."; /evidence="ECO:0000269|PubMed:41138726"; MUTAGEN 642; /note="E->K: Loss of NAD(+) hydrolase activity."; /evidence="ECO:0000269|PubMed:28334607, ECO:0000269|PubMed:31128467, ECO:0000269|PubMed:31439792, ECO:0000269|PubMed:31439793, ECO:0000269|PubMed:33053563"; MUTAGEN 685; /note="H->A: Reduced NAD(+) hydrolase activity."; /evidence="ECO:0000269|PubMed:31439792
uniprot
proteins
post_translational_modification
PTM: 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). {ECO:0000269|PubMed:30333228}.
uniprot
proteins
protein_family
SARM1 family
uniprot
proteins
pubmed
11386760
uniprot
proteins
pubmed
15123841
uniprot
proteins
pubmed
16964262
uniprot
proteins
pubmed
16985498
uniprot
proteins
pubmed
17724133
uniprot
proteins
pubmed
18089857
uniprot
proteins
pubmed
20306472
uniprot
proteins
pubmed
22145856
uniprot
proteins
pubmed
25908823
uniprot
proteins
pubmed
27671644
uniprot
proteins
pubmed
28334607
uniprot
proteins
pubmed
29395922
uniprot
proteins
pubmed
30333228
uniprot
proteins
pubmed
31128467
uniprot
proteins
pubmed
31278906
uniprot
proteins
pubmed
31439792
uniprot
proteins
pubmed
31439793
uniprot
proteins
pubmed
32049506
uniprot
proteins
pubmed
32755591
uniprot
proteins
pubmed
32828421
uniprot
proteins
pubmed
33053563
uniprot
proteins
pubmed
41138726
uniprot
proteins
pubmed
9628581
uniprot
proteins
sequence_length
724
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:20306472, ECO:0000269|PubMed:41138726}. Cell projection, axon {ECO:0000250|UniProtKB:Q6PDS3}. Cell projection, dendrite {ECO:0000250|UniProtKB:Q6PDS3}. Synapse {ECO:0000250|UniProtKB:Q6PDS3}. Mitochondrion {ECO:0000269|PubMed:20306472, ECO:0000269|PubMed:22145856}. Note=Associated with microtubules. {ECO:0000250|UniProtKB:Q6PDS3}.
uniprot
proteins