SARM1_MOUSE
ID SARM1_MOUSE Reviewed; 724 AA.
AC Q6PDS3; Q5SYG5; Q5SYG6; Q6A054; Q6SZW0; Q8BRI9;
DT 10-MAY-2005, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 150.
DE RecName: Full=NAD(+) hydrolase SARM1 {ECO:0000305};
DE Short=NADase SARM1 {ECO:0000305};
DE EC=3.2.2.6 {ECO:0000269|PubMed:28334607};
DE AltName: Full=NADP(+) hydrolase SARM1 {ECO:0000305};
DE EC=3.2.2.- {ECO:0000250|UniProtKB:Q6SZW1};
DE AltName: Full=Sterile alpha and TIR motif-containing protein 1 {ECO:0000303|Ref.1};
DE Flags: Precursor;
GN Name=Sarm1 {ECO:0000303|Ref.1, ECO:0000312|MGI:MGI:2136419};
GN Synonyms=Kiaa0524 {ECO:0000303|PubMed:15368895};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RA Bousson J.-C., Casteran C., Tiraby G.;
RT "SARM1 isoforms nucleotide sequence.";
RL Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Pancreatic islet;
RX PubMed=15368895; DOI=10.1093/dnares/11.3.205;
RA Okazaki N., Kikuno R., Ohara R., Inamoto S., Koseki H., Hiraoka S.,
RA Saga Y., Seino S., Nishimura M., Kaisho T., Hoshino K., Kitamura H.,
RA Nagase T., Ohara O., Koga H.;
RT "Prediction of the coding sequences of mouse homologues of KIAA gene: IV.
RT The complete nucleotide sequences of 500 mouse KIAA-homologous cDNAs
RT identified by screening of terminal sequences of cDNA clones randomly
RT sampled from size-fractionated libraries.";
RL DNA Res. 11:205-218(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Brain cortex;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=C57BL/6J; TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH MAPK10.
RX PubMed=17724133; DOI=10.1084/jem.20070868;
RA Kim Y., Zhou P., Qian L., Chuang J.Z., Lee J., Li C., Iadecola C.,
RA Nathan C., Ding A.;
RT "MyD88-5 links mitochondria, microtubules, and JNK3 in neurons and
RT regulates neuronal survival.";
RL J. Exp. Med. 204:2063-2074(2007).
RN [7]
RP REVIEW.
RX PubMed=18089857; DOI=10.1126/stke.4172007pe73;
RA Dalod M.;
RT "Studies of SARM1 uncover similarities between immune and neuronal
RT responses to danger.";
RL Sci. STKE 2007:PE73-PE73(2007).
RN [8]
RP FUNCTION.
RX PubMed=19587044; DOI=10.1128/jvi.00836-09;
RA Szretter K.J., Samuel M.A., Gilfillan S., Fuchs A., Colonna M.,
RA Diamond M.S.;
RT "The immune adaptor molecule SARM modulates tumor necrosis factor alpha
RT production and microglia activation in the brainstem and restricts West
RT Nile virus pathogenesis.";
RL J. Virol. 83:9329-9338(2009).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-548 AND SER-558, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [10]
RP FUNCTION, IDENTIFICATION BY MASS SPECTROMETRY, INTERACTION WITH SDC2, AND
RP TISSUE SPECIFICITY.
RX PubMed=21555464; DOI=10.1083/jcb.201008050;
RA Chen C.Y., Lin C.W., Chang C.Y., Jiang S.T., Hsueh Y.P.;
RT "Sarm1, a negative regulator of innate immunity, interacts with syndecan-2
RT and regulates neuronal morphology.";
RL J. Cell Biol. 193:769-784(2011).
RN [11]
RP REVIEW.
RX PubMed=22837513; DOI=10.1126/science.1226150;
RA Yu X.M., Luo L.;
RT "Neuroscience. dSarm-ing axon degeneration.";
RL Science 337:418-419(2012).
RN [12]
RP FUNCTION, SUBCELLULAR LOCATION, AND DISRUPTION PHENOTYPE.
RX PubMed=22678360; DOI=10.1126/science.1223899;
RA Osterloh J.M., Yang J., Rooney T.M., Fox A.N., Adalbert R., Powell E.H.,
RA Sheehan A.E., Avery M.A., Hackett R., Logan M.A., MacDonald J.M.,
RA Ziegenfuss J.S., Milde S., Hou Y.J., Nathan C., Ding A., Brown R.H. Jr.,
RA Conforti L., Coleman M., Tessier-Lavigne M., Zuechner S., Freeman M.R.;
RT "dSarm/Sarm1 is required for activation of an injury-induced axon death
RT pathway.";
RL Science 337:481-484(2012).
RN [13]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=25818290; DOI=10.1016/j.celrep.2015.02.060;
RA Gilley J., Orsomando G., Nascimento-Ferreira I., Coleman M.P.;
RT "Absence of SARM1 rescues development and survival of NMNAT2-deficient
RT axons.";
RL Cell Rep. 10:1974-1981(2015).
RN [14]
RP FUNCTION.
RX PubMed=26686637; DOI=10.1016/j.celrep.2015.11.032;
RA Loreto A., Di Stefano M., Gering M., Conforti L.;
RT "Wallerian Degeneration Is Executed by an NMN-SARM1-Dependent Late Ca(2+)
RT Influx but Only Modestly Influenced by Mitochondria.";
RL Cell Rep. 13:2539-2552(2015).
RN [15]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=26423149; DOI=10.4049/jimmunol.1500953;
RA Mukherjee P., Winkler C.W., Taylor K.G., Woods T.A., Nair V., Khan B.A.,
RA Peterson K.E.;
RT "SARM1, Not MyD88, Mediates TLR7/TLR9-Induced Apoptosis in Neurons.";
RL J. Immunol. 195:4913-4921(2015).
RN [16]
RP DISRUPTION PHENOTYPE.
RX PubMed=26912636; DOI=10.1093/brain/aww001;
RA Henninger N., Bouley J., Sikoglu E.M., An J., Moore C.M., King J.A.,
RA Bowser R., Freeman M.R., Brown R.H. Jr.;
RT "Attenuated traumatic axonal injury and improved functional outcome after
RT traumatic brain injury in mice lacking Sarm1.";
RL Brain 139:1094-1105(2016).
RN [17]
RP DISRUPTION PHENOTYPE.
RX PubMed=27797810; DOI=10.1093/brain/aww251;
RA Geisler S., Doan R.A., Strickland A., Huang X., Milbrandt J., DiAntonio A.;
RT "Prevention of vincristine-induced peripheral neuropathy by genetic
RT deletion of SARM1 in mice.";
RL Brain 139:3092-3108(2016).
RN [18]
RP FUNCTION.
RX PubMed=27735788; DOI=10.7554/elife.19749;
RA Sasaki Y., Nakagawa T., Mao X., DiAntonio A., Milbrandt J.;
RT "NMNAT1 inhibits axon degeneration via blockade of SARM1-mediated NAD+
RT depletion.";
RL Elife 5:0-0(2016).
RN [19]
RP DISRUPTION PHENOTYPE.
RX PubMed=28978465; DOI=10.1016/j.celrep.2017.09.027;
RA Gilley J., Ribchester R.R., Coleman M.P.;
RT "Sarm1 deletion, but not WldS, confers lifelong rescue in a mouse model of
RT severe axonopathy.";
RL Cell Rep. 21:10-16(2017).
RN [20]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=28334607; DOI=10.1016/j.neuron.2017.02.022;
RA Essuman K., Summers D.W., Sasaki Y., Mao X., DiAntonio A., Milbrandt J.;
RT "The SARM1 Toll/Interleukin-1 receptor domain possesses intrinsic NAD+
RT cleavage activity that promotes pathological axonal degeneration.";
RL Neuron 93:1334-1343(2017).
RN [21]
RP DISRUPTION PHENOTYPE.
RX PubMed=31439642; DOI=10.2337/db18-1233;
RA Cheng Y., Liu J., Luan Y., Liu Z., Lai H., Zhong W., Yang Y., Yu H.,
RA Feng N., Wang H., Huang R., He Z., Yan M., Zhang F., Sun Y.G., Yin H.,
RA Guo F., Zhai Q.;
RT "Sarm1 gene deficiency attenuates diabetic peripheral neuropathy in mice.";
RL Diabetes 68:2120-2130(2019).
RN [22]
RP DISRUPTION PHENOTYPE.
RX PubMed=32584865; DOI=10.1371/journal.pone.0235110;
RA Viar K., Njoku D., Secor McVoy J., Oh U.;
RT "Sarm1 knockout protects against early but not late axonal degeneration in
RT experimental allergic encephalomyelitis.";
RL PLoS ONE 15:e0235110-e0235110(2020).
RN [23]
RP FUNCTION, DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY.
RX PubMed=32312889; DOI=10.26508/lsa.201900618;
RA Ozaki E., Gibbons L., Neto N.G., Kenna P., Carty M., Humphries M.,
RA Humphries P., Campbell M., Monaghan M., Bowie A., Doyle S.L.;
RT "SARM1 deficiency promotes rod and cone photoreceptor cell survival in a
RT model of retinal degeneration.";
RL Life. Sci Alliance 3:0-0(2020).
CC -!- FUNCTION: NAD(+) hydrolase, which plays a key role in axonal
CC degeneration following injury by regulating NAD(+) metabolism
CC (PubMed:25818290, PubMed:26686637, PubMed:27735788, PubMed:32312889).
CC Acts as a negative regulator of MYD88- and TRIF-dependent toll-like
CC receptor signaling pathway by promoting Wallerian degeneration, an
CC injury-induced form of programmed subcellular death which involves
CC degeneration of an axon distal to the injury site (PubMed:21555464,
CC PubMed:22678360, PubMed:25818290, PubMed:26686637, PubMed:26423149).
CC Wallerian degeneration is triggered by NAD(+) depletion: in response to
CC injury, SARM1 is activated and catalyzes cleavage of NAD(+) into ADP-D-
CC ribose (ADPR), cyclic ADPR (cADPR) and nicotinamide; NAD(+) cleavage
CC promoting cytoskeletal degradation and axon destruction
CC (PubMed:28334607). Also able to hydrolyze NADP(+), but not other
CC NAD(+)-related molecules (By similarity). Can activate neuronal cell
CC death in response to stress (PubMed:19587044). Regulates dendritic
CC arborization through the MAPK4-JNK pathway (PubMed:17724133,
CC PubMed:21555464). Involved in innate immune response: inhibits both
CC TICAM1/TRIF- and MYD88-dependent activation of JUN/AP-1, TRIF-dependent
CC activation of NF-kappa-B and IRF3, and the phosphorylation of
CC MAPK14/p38 (PubMed:21555464). {ECO:0000250|UniProtKB:Q6SZW1,
CC ECO:0000269|PubMed:17724133, ECO:0000269|PubMed:19587044,
CC ECO:0000269|PubMed:21555464, ECO:0000269|PubMed:22678360,
CC ECO:0000269|PubMed:25818290, ECO:0000269|PubMed:26423149,
CC ECO:0000269|PubMed:26686637, ECO:0000269|PubMed:27735788,
CC ECO:0000269|PubMed:28334607, ECO:0000269|PubMed:32312889}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + NAD(+) = ADP-D-ribose + H(+) + nicotinamide;
CC Xref=Rhea:RHEA:16301, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:17154, ChEBI:CHEBI:57540, ChEBI:CHEBI:57967; EC=3.2.2.6;
CC Evidence={ECO:0000269|PubMed:28334607};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16302;
CC Evidence={ECO:0000269|PubMed:28334607};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=NAD(+) = cyclic ADP-ribose + H(+) + nicotinamide;
CC Xref=Rhea:RHEA:38611, ChEBI:CHEBI:15378, ChEBI:CHEBI:17154,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:73672;
CC Evidence={ECO:0000250|UniProtKB:Q6SZW1};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38612;
CC Evidence={ECO:0000250|UniProtKB:Q6SZW1};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + NADP(+) = ADP-D-ribose 2'-phosphate + H(+) +
CC nicotinamide; Xref=Rhea:RHEA:19849, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:17154, ChEBI:CHEBI:58349,
CC ChEBI:CHEBI:58673; Evidence={ECO:0000250|UniProtKB:Q6SZW1};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19850;
CC Evidence={ECO:0000250|UniProtKB:Q6SZW1};
CC -!- ACTIVITY REGULATION: Autoinhibited: in the inactive state, the
CC enzymatic TIR domain is held apart by the autoinhibiting ARM repeats.
CC NAD(+)-binding to ARM repeats maintains an inactive state by promoting
CC interaction between ARM repeats and the TIR domain, thereby
CC facilitating inhibition of the enzymatic TIR domain. Following
CC activation, possibly by nicotinamide mononucleotide (NMN), auto-
CC inhibitory interactions are released, allowing self-association of the
CC TIR domains and subsequent activation of the NAD(+) hydrolase (NADase)
CC activity. Self-association of TIR domains is facilitated by the octamer
CC of SAM domains. {ECO:0000250|UniProtKB:Q6SZW1}.
CC -!- SUBUNIT: Homooctamer; forms an octomeric ring via SAM domains (By
CC similarity). Interacts with TICAM1/TRIF and thereby interferes with
CC TICAM1/TRIF function (By similarity). Interacts with SDC2 (via
CC cytoplasmic domain) and MAPK10/JNK3 (PubMed:17724133, PubMed:21555464).
CC {ECO:0000250|UniProtKB:Q6SZW1, ECO:0000269|PubMed:17724133,
CC ECO:0000269|PubMed:21555464}.
CC -!- INTERACTION:
CC Q6PDS3; Q96A33: CCDC47; Xeno; NbExp=2; IntAct=EBI-6117196, EBI-720151;
CC Q6PDS3; Q9H3K2: GHITM; Xeno; NbExp=2; IntAct=EBI-6117196, EBI-2868909;
CC Q6PDS3; O43187: IRAK2; Xeno; NbExp=2; IntAct=EBI-6117196, EBI-447733;
CC Q6PDS3; Q86UT6: NLRX1; Xeno; NbExp=2; IntAct=EBI-6117196, EBI-3893071;
CC Q6PDS3; P46977: STT3A; Xeno; NbExp=2; IntAct=EBI-6117196, EBI-719212;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:17724133}. Cell
CC projection, axon {ECO:0000269|PubMed:22678360}. Cell projection,
CC dendrite {ECO:0000269|PubMed:21555464}. Synapse
CC {ECO:0000269|PubMed:22678360}. Mitochondrion
CC {ECO:0000269|PubMed:17724133, ECO:0000269|PubMed:26423149}.
CC Note=Associated with microtubules. {ECO:0000269|PubMed:17724133}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=Q6PDS3-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q6PDS3-2; Sequence=VSP_013604;
CC Name=3;
CC IsoId=Q6PDS3-3; Sequence=VSP_013605;
CC Name=4;
CC IsoId=Q6PDS3-4; Sequence=VSP_013606, VSP_013607;
CC -!- TISSUE SPECIFICITY: Widely expressed in the brain and neurons (at
CC protein level) (PubMed:21555464). Expressed in photoreceptor cells of
CC the neural retina (PubMed:32312889). {ECO:0000269|PubMed:21555464,
CC ECO:0000269|PubMed:32312889}.
CC -!- INDUCTION: Down-regulated in sciatic nerve of mice with diabetic
CC peripheral neuropathy (at protein level).
CC {ECO:0000269|PubMed:31439642}.
CC -!- DOMAIN: The TIR domain mediates NAD(+) hydrolase (NADase) activity.
CC Self-association of TIR domains is required for NADase activity.
CC {ECO:0000250|UniProtKB:Q6SZW1}.
CC -!- DOMAIN: The ARM repeats inhibit the NAD(+) hydrolase (NADase) activity
CC by binding to NAD(+): NAD(+)-binding to ARM repeats facilitates
CC inhibition of the TIR domain NADase through their domain interface. In
CC contrast to classical ARM repeats, the last helix of ARM 6 does not
CC fold back to interact with the first two helices, but instead turns
CC towards the N-terminus of SARM1. As a result, the two following motifs
CC ARM 7 and ARM 8 reverse their directions and lie perpendicularly.
CC Moreover, ARM repeats interact with different domains not only within
CC each protomer but also of the adjacent ones.
CC {ECO:0000250|UniProtKB:Q6SZW1}.
CC -!- PTM: Phosphorylation at Ser-548 by JNK kinases (MAPK8, MAPK9 and /or
CC MAPK10) enhance the NAD(+) hydrolase (NADase) activity. Phosphorylation
CC at Ser-548 and subsequent activation takes place in response to
CC oxidative stress conditions and inhibits mitochondrial respiration.
CC {ECO:0000250|UniProtKB:Q6SZW1}.
CC -!- DISRUPTION PHENOTYPE: Absence of Sarm1 provides a level of protection
CC against axon degeneration (PubMed:22678360, PubMed:26912636,
CC PubMed:28978465). Genetic deletion blocks Wallerian degeneration of
CC sciatic nerve and cultured superior cervical ganglia and peripheral
CC polyneuropathy induced by vincristine (PubMed:22678360,
CC PubMed:27797810). Severed Sarm1 null axons are able to persist up to 72
CC hours after axotomy, whereas wild-type axons degenerate within 8 hours
CC (PubMed:22678360). Similarly, axons appear to be protected from
CC degeneration in a sciatic nerve lesion model, lasting up to 14 days
CC compared with 3 days for wild type (PubMed:22678360). Mice display
CC improved traumatic brain injury-associated phenotypes after injury:
CC mice develop fewer beta-amyloid precursor protein aggregates in axons
CC of the corpus callosum after traumatic brain injury and show improved
CC axonal integrity (PubMed:26912636). Mice show some protection against
CC early but not late axonal degeneration in experimental allergic
CC encephalomyelitis mouse model (PubMed:32584865). Mice exhibit normal
CC glucose metabolism and pain sensitivity but show attenuated diabetic
CC peripheral neuropathy (PubMed:31439642). Mice lacking both Sarm1 and
CC Nmnat2 are viable and survive: Sarm1 deficiency corrects axon outgrowth
CC in mice lacking Nmnat2, independently of NMNAT metabolites, preventing
CC perinatal lethality (PubMed:25818290). Mice lacking both Rho and Sarm1
CC show a level of protection against retinal degeneration induced by the
CC absence of Rho: the absence of Sarm1 promoting rod and cone
CC photoreceptor cell survival (PubMed:32312889).
CC {ECO:0000269|PubMed:22678360, ECO:0000269|PubMed:25818290,
CC ECO:0000269|PubMed:26912636, ECO:0000269|PubMed:27797810,
CC ECO:0000269|PubMed:28978465, ECO:0000269|PubMed:31439642,
CC ECO:0000269|PubMed:32312889, ECO:0000269|PubMed:32584865}.
CC -!- SIMILARITY: Belongs to the SARM1 family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAD32242.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=CAI25546.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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DR EMBL; AY444167; AAR17521.1; -; mRNA.
DR EMBL; AK172964; BAD32242.1; ALT_INIT; Transcribed_RNA.
DR EMBL; AK044113; BAC31784.1; -; mRNA.
DR EMBL; AL591177; CAI25544.1; -; Genomic_DNA.
DR EMBL; AL591177; CAI25545.1; -; Genomic_DNA.
DR EMBL; AL591177; CAI25546.1; ALT_SEQ; Genomic_DNA.
DR EMBL; BC058534; AAH58534.1; -; mRNA.
DR EMBL; BC080850; AAH80850.1; -; mRNA.
DR CCDS; CCDS25105.1; -. [Q6PDS3-1]
DR CCDS; CCDS48857.1; -. [Q6PDS3-3]
DR RefSeq; NP_001161993.1; NM_001168521.1. [Q6PDS3-3]
DR RefSeq; NP_766383.2; NM_172795.3. [Q6PDS3-1]
DR AlphaFoldDB; Q6PDS3; -.
DR SMR; Q6PDS3; -.
DR BioGRID; 231917; 3.
DR IntAct; Q6PDS3; 11.
DR STRING; 10090.ENSMUSP00000103922; -.
DR ChEMBL; CHEMBL4523348; -.
DR iPTMnet; Q6PDS3; -.
DR PhosphoSitePlus; Q6PDS3; -.
DR MaxQB; Q6PDS3; -.
DR PeptideAtlas; Q6PDS3; -.
DR PRIDE; Q6PDS3; -.
DR ProteomicsDB; 256727; -. [Q6PDS3-1]
DR ProteomicsDB; 256728; -. [Q6PDS3-2]
DR ProteomicsDB; 256729; -. [Q6PDS3-3]
DR ProteomicsDB; 256730; -. [Q6PDS3-4]
DR Antibodypedia; 14061; 208 antibodies from 34 providers.
DR DNASU; 237868; -.
DR Ensembl; ENSMUST00000061174; ENSMUSP00000051059; ENSMUSG00000050132. [Q6PDS3-1]
DR Ensembl; ENSMUST00000108287; ENSMUSP00000103922; ENSMUSG00000050132. [Q6PDS3-3]
DR GeneID; 237868; -.
DR KEGG; mmu:237868; -.
DR UCSC; uc007kjh.2; mouse. [Q6PDS3-4]
DR UCSC; uc007kji.2; mouse. [Q6PDS3-1]
DR UCSC; uc007kjj.2; mouse. [Q6PDS3-3]
DR CTD; 23098; -.
DR MGI; MGI:2136419; Sarm1.
DR VEuPathDB; HostDB:ENSMUSG00000050132; -.
DR eggNOG; KOG3678; Eukaryota.
DR GeneTree; ENSGT00390000004155; -.
DR HOGENOM; CLU_003286_2_0_1; -.
DR InParanoid; Q6PDS3; -.
DR OMA; CVPSWKE; -.
DR OrthoDB; 206466at2759; -.
DR PhylomeDB; Q6PDS3; -.
DR TreeFam; TF315263; -.
DR Reactome; R-MMU-166166; MyD88-independent TLR4 cascade.
DR Reactome; R-MMU-936964; Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon.
DR Reactome; R-MMU-937041; IKK complex recruitment mediated by RIP1.
DR Reactome; R-MMU-937072; TRAF6-mediated induction of TAK1 complex within TLR4 complex.
DR BioGRID-ORCS; 237868; 1 hit in 71 CRISPR screens.
DR ChiTaRS; Sarm1; mouse.
DR PRO; PR:Q6PDS3; -.
DR Proteomes; UP000000589; Chromosome 11.
DR RNAct; Q6PDS3; protein.
DR Bgee; ENSMUSG00000050132; Expressed in superior cervical ganglion and 77 other tissues.
DR Genevisible; Q6PDS3; MM.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0030424; C:axon; IEA:UniProtKB-SubCell.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0030425; C:dendrite; IMP:UniProtKB.
DR GO; GO:0031315; C:extrinsic component of mitochondrial outer membrane; IDA:MGI.
DR GO; GO:0005874; C:microtubule; IDA:UniProtKB.
DR GO; GO:0015630; C:microtubule cytoskeleton; IDA:MGI.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0045202; C:synapse; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0050135; F:NAD(P)+ nucleosidase activity; IEA:UniProtKB-EC.
DR GO; GO:0003953; F:NAD+ nucleosidase activity; IDA:UniProtKB.
DR GO; GO:0061809; F:NAD+ nucleotidase, cyclic ADP-ribose generating; ISS:UniProtKB.
DR GO; GO:0035591; F:signaling adaptor activity; IEA:InterPro.
DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0019677; P:NAD catabolic process; IDA:UniProtKB.
DR GO; GO:0034128; P:negative regulation of MyD88-independent toll-like receptor signaling pathway; IEA:InterPro.
DR GO; GO:0007399; P:nervous system development; IEA:UniProtKB-KW.
DR GO; GO:1901216; P:positive regulation of neuron death; IMP:UniProtKB.
DR GO; GO:0048814; P:regulation of dendrite morphogenesis; IMP:UniProtKB.
DR GO; GO:0043523; P:regulation of neuron apoptotic process; IMP:MGI.
DR GO; GO:1901214; P:regulation of neuron death; IMP:UniProtKB.
DR GO; GO:0048678; P:response to axon injury; ISS:UniProtKB.
DR GO; GO:0009749; P:response to glucose; IMP:MGI.
DR GO; GO:0007165; P:signal transduction; IEA:InterPro.
DR Gene3D; 1.10.150.50; -; 2.
DR Gene3D; 1.25.10.10; -; 1.
DR Gene3D; 3.40.50.10140; -; 1.
DR InterPro; IPR011989; ARM-like.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR001660; SAM.
DR InterPro; IPR013761; SAM/pointed_sf.
DR InterPro; IPR039184; SARM1.
DR InterPro; IPR000157; TIR_dom.
DR InterPro; IPR035897; Toll_tir_struct_dom_sf.
DR PANTHER; PTHR22998; PTHR22998; 1.
DR Pfam; PF07647; SAM_2; 2.
DR Pfam; PF13676; TIR_2; 1.
DR SMART; SM00454; SAM; 2.
DR SMART; SM00255; TIR; 1.
DR SUPFAM; SSF47769; SSF47769; 2.
DR SUPFAM; SSF48371; SSF48371; 1.
DR SUPFAM; SSF52200; SSF52200; 1.
DR PROSITE; PS50105; SAM_DOMAIN; 2.
DR PROSITE; PS50104; TIR; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell projection; Cytoplasm; Differentiation;
KW Hydrolase; Immunity; Innate immunity; Mitochondrion; NAD; Neurogenesis;
KW Phosphoprotein; Reference proteome; Repeat; Synapse; Transit peptide.
FT TRANSIT 1..27
FT /note="Mitochondrion"
FT /evidence="ECO:0000250|UniProtKB:Q6SZW1"
FT CHAIN 28..724
FT /note="NAD(+) hydrolase SARM1"
FT /id="PRO_0000097590"
FT REPEAT 60..100
FT /note="ARM 1"
FT /evidence="ECO:0000255"
FT REPEAT 114..153
FT /note="ARM 2"
FT /evidence="ECO:0000255"
FT REPEAT 155..193
FT /note="ARM 3"
FT /evidence="ECO:0000255"
FT REPEAT 196..235
FT /note="ARM 4"
FT /evidence="ECO:0000255"
FT REPEAT 237..280
FT /note="ARM 5"
FT /evidence="ECO:0000255"
FT REPEAT 281..314
FT /note="ARM 6"
FT /evidence="ECO:0000255"
FT REPEAT 315..354
FT /note="ARM 7"
FT /evidence="ECO:0000255"
FT REPEAT 359..402
FT /note="ARM 8"
FT /evidence="ECO:0000255"
FT DOMAIN 412..476
FT /note="SAM 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00184"
FT DOMAIN 486..548
FT /note="SAM 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00184"
FT DOMAIN 560..703
FT /note="TIR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204"
FT REGION 24..56
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 703..724
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 642
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204"
FT BINDING 103
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /ligand_label="1"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000250|UniProtKB:Q6SZW1"
FT BINDING 110
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /ligand_label="1"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000250|UniProtKB:Q6SZW1"
FT BINDING 149..157
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /ligand_label="1"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000250|UniProtKB:Q6SZW1"
FT BINDING 190..193
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /ligand_label="1"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000250|UniProtKB:Q6SZW1"
FT BINDING 569..570
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /ligand_label="2"
FT /ligand_note="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q6SZW1"
FT BINDING 599
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /ligand_label="2"
FT /ligand_note="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q6SZW1"
FT MOD_RES 548
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 558
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT VAR_SEQ 1..536
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000305"
FT /id="VSP_013606"
FT VAR_SEQ 435..439
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15368895"
FT /id="VSP_013604"
FT VAR_SEQ 537..543
FT /note="RILSAAR -> MSLSLAP (in isoform 4)"
FT /evidence="ECO:0000305"
FT /id="VSP_013607"
FT VAR_SEQ 543
FT /note="R -> RGHFAQTGLRSLRRPSLHDDGPRDKQWGRATLTSMSLSLAP (in
FT isoform 3)"
FT /evidence="ECO:0000303|Ref.1"
FT /id="VSP_013605"
FT CONFLICT 61
FT /note="V -> A (in Ref. 1; AAR17521)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 724 AA; 79606 MW; 9A5BF03ED22E6102 CRC64;
MVLTLLFSAY KLCRFFTMSG PRPGADRLTV PGPDRSGGAS PWWAAGGRGS REVSPGVGTE
VQGALERSLP ELQQALSELK QASAARAVGA GLAEVFQLVE EAWLLPAVGR EVAQGLCDAI
RLDGGLDLLL RLLQAPELET RVQAARLLEQ ILVAENRDRV ARIGLGVILN LAKEREPVEL
ARSVAGILEH MFKHSEETCQ RLVAAGGLDA VLYWCRRTDP ALLRHCALAL ANCALHGGQT
VQRCMVEKRA AEWLFPLAFS KEDELLRLHA CLAVAVLATN KEVEREVEHS GTLALVEPLV
ASLDPGRFAR CLVDASDTSQ GRGPDDLQSL VLLLDSSRLE AQCIGAFYLC AEAAIKSLQG
KTKVFSDIGA IQSLKRLVSY STNGTTSALA KRALRLLGEE VPRRILPCVA SWKEAEVQTW
LQQIGFSQYC ENFREQQVDG DLLLRLTDEE LQTDLGMKSS ITRKRFFREL TELKTFASYA
TCDRSNLADW LGSLDPRFRQ YTYGLVSCGL DRSLLHRVSE QQLLEDCGIR LGVHRTRILS
AAREMLHSPL PCTGGKLSGD TPDVFISYRR NSGSQLASLL KVHLQLHGFS VFIDVEKLEA
GKFEDKLIQS VIAARNFVLV LSAGALDKCM QDHDCKDWVH KEIVTALSCG KNIVPIIDGF
EWPEPQALPE DMQAVLTFNG IKWSHEYQEA TIEKIIRFLQ GRPSQDSSAG SDTSLEGATP
MGLP
