SARM1_HUMAN
ID SARM1_HUMAN Reviewed; 724 AA.
AC Q6SZW1; O60277; Q7LGG3; Q9NXY5;
DT 10-MAY-2005, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 148.
DE RecName: Full=NAD(+) hydrolase SARM1 {ECO:0000305};
DE Short=NADase SARM1 {ECO:0000305};
DE Short=hSARM1 {ECO:0000303|PubMed:31439792};
DE EC=3.2.2.6 {ECO:0000269|PubMed:28334607, ECO:0000269|PubMed:30333228, ECO:0000269|PubMed:31128467, ECO:0000269|PubMed:31439792, ECO:0000269|PubMed:31439793, ECO:0000269|PubMed:33053563};
DE AltName: Full=NADP(+) hydrolase SARM1 {ECO:0000305};
DE EC=3.2.2.- {ECO:0000269|PubMed:29395922};
DE AltName: Full=Sterile alpha and Armadillo repeat protein {ECO:0000303|PubMed:11386760};
DE AltName: Full=Sterile alpha and TIR motif-containing protein 1 {ECO:0000303|PubMed:18089857, ECO:0000303|Ref.2};
DE AltName: Full=Sterile alpha motif domain-containing protein 2 {ECO:0000303|PubMed:17724133};
DE Short=MyD88-5 {ECO:0000303|PubMed:17724133};
DE Short=SAM domain-containing protein 2 {ECO:0000312|HGNC:HGNC:17074};
DE AltName: Full=Tir-1 homolog {ECO:0000303|PubMed:15123841};
DE Short=HsTIR {ECO:0000303|PubMed:27671644};
DE Flags: Precursor;
GN Name=SARM1 {ECO:0000303|PubMed:18089857, ECO:0000303|Ref.2,
GN ECO:0000312|HGNC:HGNC:17074};
GN Synonyms=KIAA0524 {ECO:0000303|PubMed:9628581},
GN SAMD2 {ECO:0000312|HGNC:HGNC:17074}, SARM {ECO:0000303|PubMed:11386760};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND TISSUE SPECIFICITY.
RC TISSUE=Brain;
RX PubMed=11386760; DOI=10.1006/geno.2001.6548;
RA Mink M., Fogelgren B., Olszewski K., Maroy P., Csiszar K.;
RT "A novel human gene (SARM) at chromosome 17q11 encodes a protein with a SAM
RT motif and structural similarity to Armadillo/beta-catenin that is conserved
RT in mouse, Drosophila, and Caenorhabditis elegans.";
RL Genomics 74:234-244(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Bousson J.-C., Casteran C., Tiraby G.;
RT "SARM1 isoforms nucleotide sequence.";
RL Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 127-724.
RC TISSUE=Brain;
RX PubMed=9628581; DOI=10.1093/dnares/5.1.31;
RA Nagase T., Ishikawa K., Miyajima N., Tanaka A., Kotani H., Nomura N.,
RA Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. IX. The
RT complete sequences of 100 new cDNA clones from brain which can code for
RT large proteins in vitro.";
RL DNA Res. 5:31-39(1998).
RN [4]
RP FUNCTION.
RX PubMed=15123841; DOI=10.1073/pnas.0308625101;
RA Liberati N.T., Fitzgerald K.A., Kim D.H., Feinbaum R., Golenbock D.T.,
RA Ausubel F.M.;
RT "Requirement for a conserved Toll/interleukin-1 resistance domain protein
RT in the Caenorhabditis elegans immune response.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:6593-6598(2004).
RN [5]
RP FUNCTION, AND INTERACTION WITH TICAM1.
RX PubMed=16964262; DOI=10.1038/ni1382;
RA Carty M., Goodbody R., Schroeder M., Stack J., Moynagh P.N., Bowie A.G.;
RT "The human adaptor SARM negatively regulates adaptor protein TRIF-dependent
RT Toll-like receptor signaling.";
RL Nat. Immunol. 7:1074-1081(2006).
RN [6]
RP REVIEW.
RX PubMed=16985498; DOI=10.1038/ni1006-1023;
RA O'Neill L.A.J.;
RT "DisSARMing Toll-like receptor signaling.";
RL Nat. Immunol. 7:1023-1025(2006).
RN [7]
RP TISSUE SPECIFICITY.
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 [8]
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 [9]
RP FUNCTION, SUBCELLULAR LOCATION, AND INDUCTION.
RX PubMed=20306472; DOI=10.1002/eji.200940034;
RA Peng J., Yuan Q., Lin B., Panneerselvam P., Wang X., Luan X.L., Lim S.K.,
RA Leung B.P., Ho B., Ding J.L.;
RT "SARM inhibits both TRIF- and MyD88-mediated AP-1 activation.";
RL Eur. J. Immunol. 40:1738-1747(2010).
RN [10]
RP SUBCELLULAR LOCATION, MITOCHONDRIAL TRANSIT PEPTIDE CLEAVAGE SITE, AND
RP MUTAGENESIS OF LYS-11; ARG-14; ARG-22 AND ARG-27.
RX PubMed=22145856; DOI=10.1042/bj20111653;
RA Panneerselvam P., Singh L.P., Ho B., Chen J., Ding J.L.;
RT "Targeting of pro-apoptotic TLR adaptor SARM to mitochondria: definition of
RT the critical region and residues in the signal sequence.";
RL Biochem. J. 442:263-271(2012).
RN [11]
RP FUNCTION.
RX PubMed=25908823; DOI=10.1126/science.1258366;
RA Gerdts J., Brace E.J., Sasaki Y., DiAntonio A., Milbrandt J.;
RT "SARM1 activation triggers axon degeneration locally via NAD+
RT destruction.";
RL Science 348:453-457(2015).
RN [12]
RP FUNCTION, ACTIVITY REGULATION, DOMAIN, AND MUTAGENESIS OF GLU-596; LYS-597;
RP GLY-601; GLU-604; LEU-626; ASP-627; LYS-628; CYS-629 AND ASP-632.
RX PubMed=27671644; DOI=10.1073/pnas.1601506113;
RA Summers D.W., Gibson D.A., DiAntonio A., Milbrandt J.;
RT "SARM1-specific motifs in the TIR domain enable NAD+ loss and regulate
RT injury-induced SARM1 activation.";
RL Proc. Natl. Acad. Sci. U.S.A. 113:E6271-E6280(2016).
RN [13]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, ACTIVE SITE,
RP BIOPHYSICOCHEMICAL PROPERTIES, AND MUTAGENESIS OF GLU-596; GLY-601 AND
RP GLU-642.
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 [14]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=29395922; DOI=10.1016/j.cub.2017.12.024;
RA Essuman K., Summers D.W., Sasaki Y., Mao X., Yim A.K.Y., DiAntonio A.,
RA Milbrandt J.;
RT "TIR domain proteins are an ancient family of NAD+-consuming enzymes.";
RL Curr. Biol. 28:421-430(2018).
RN [15]
RP FUNCTION, CATALYTIC ACTIVITY, PHOSPHORYLATION AT SER-548, AND MUTAGENESIS
RP OF SER-408; SER-411; THR-419; SER-427; SER-432; THR-447; THR-453; THR-462;
RP THR-471; THR-475; SER-480; THR-481; SER-485; SER-493; THR-502; SER-507;
RP SER-513; SER-519; THR-540 AND SER-548.
RX PubMed=30333228; DOI=10.1074/jbc.ra118.004578;
RA Murata H., Khine C.C., Nishikawa A., Yamamoto K.I., Kinoshita R.,
RA Sakaguchi M.;
RT "c-Jun N-terminal kinase (JNK)-mediated phosphorylation of SARM1 regulates
RT NAD+ cleavage activity to inhibit mitochondrial respiration.";
RL J. Biol. Chem. 293:18933-18943(2018).
RN [16]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND MUTAGENESIS OF
RP GLU-642.
RX PubMed=31128467; DOI=10.1016/j.isci.2019.05.001;
RA Zhao Z.Y., Xie X.J., Li W.H., Liu J., Chen Z., Zhang B., Li T., Li S.L.,
RA Lu J.G., Zhang L., Zhang L.H., Xu Z., Lee H.C., Zhao Y.J.;
RT "A cell-permeant mimetic of NMN activates SARM1 to produce cyclic ADP-
RT ribose and induce non-apoptotic cell death.";
RL IScience 15:452-466(2019).
RN [17]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF GLU-642.
RX PubMed=31439793; DOI=10.1126/science.aax1771;
RA Wan L., Essuman K., Anderson R.G., Sasaki Y., Monteiro F., Chung E.H.,
RA Osborne Nishimura E., DiAntonio A., Milbrandt J., Dangl J.L.,
RA Nishimura M.T.;
RT "TIR domains of plant immune receptors are NAD+-cleaving enzymes that
RT promote cell death.";
RL Science 365:799-803(2019).
RN [18]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=32049506; DOI=10.1021/acs.biochem.9b01078;
RA Loring H.S., Icso J.D., Nemmara V.V., Thompson P.R.;
RT "Initial kinetic characterization of sterile alpha and Toll/interleukin
RT receptor motif-containing protein 1.";
RL Biochemistry 59:933-942(2020).
RN [19]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND MUTAGENESIS OF
RP CYS-629 AND CYS-635.
RX PubMed=32828421; DOI=10.1016/j.bmc.2020.115644;
RA Loring H.S., Parelkar S.S., Mondal S., Thompson P.R.;
RT "Identification of the first noncompetitive SARM1 inhibitors.";
RL Bioorg. Med. Chem. 28:115644-115644(2020).
RN [20] {ECO:0007744|PDB:6QWV}
RP X-RAY CRYSTALLOGRAPHY (2.47 ANGSTROMS) OF 387-548, SUBUNIT, ACTIVITY
RP REGULATION, DOMAIN, AND MUTAGENESIS OF ASP-454; 461-ILE--LYS-464; ILE-461;
RP LYS-464; 531-LEU--VAL-533; LEU-531 AND VAL-533.
RX PubMed=31278906; DOI=10.1016/j.jmb.2019.06.030;
RA Sporny M., Guez-Haddad J., Lebendiker M., Ulisse V., Volf A., Mim C.,
RA Isupov M.N., Opatowsky Y.;
RT "Structural evidence for an octameric ring arrangement of SARM1.";
RL J. Mol. Biol. 431:3591-3605(2019).
RN [21] {ECO:0007744|PDB:6O0Q, ECO:0007744|PDB:6O0R, ECO:0007744|PDB:6O0S, ECO:0007744|PDB:6O0T, ECO:0007744|PDB:6O0U, ECO:0007744|PDB:6O0V, ECO:0007744|PDB:6O1B}
RP X-RAY CRYSTALLOGRAPHY (1.67 ANGSTROMS) OF 560-700, FUNCTION, CATALYTIC
RP ACTIVITY, ACTIVE SITE, SUBUNIT, ACTIVITY REGULATION, AND MUTAGENESIS OF
RP TYR-568; 569-ARG-ARG-570; ARG-569; LEU-579; ASP-594; GLU-596; GLY-601;
RP GLU-642 AND HIS-685.
RX PubMed=31439792; DOI=10.1126/science.aax1911;
RA Horsefield S., Burdett H., Zhang X., Manik M.K., Shi Y., Chen J., Qi T.,
RA Gilley J., Lai J.S., Rank M.X., Casey L.W., Gu W., Ericsson D.J., Foley G.,
RA Hughes R.O., Bosanac T., von Itzstein M., Rathjen J.P., Nanson J.D.,
RA Boden M., Dry I.B., Williams S.J., Staskawicz B.J., Coleman M.P., Ve T.,
RA Dodds P.N., Kobe B.;
RT "NAD+ cleavage activity by animal and plant TIR domains in cell death
RT pathways.";
RL Science 365:793-799(2019).
RN [22] {ECO:0007744|PDB:6WPK}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.30 ANGSTROMS) OF 49-724, ACTIVITY
RP REGULATION, AND SUBUNIT.
RX PubMed=32755591; DOI=10.1016/j.celrep.2020.107999;
RA Bratkowski M., Xie T., Thayer D.A., Lad S., Mathur P., Yang Y.S., Danko G.,
RA Burdett T.C., Danao J., Cantor A., Kozak J.A., Brown S.P., Bai X.,
RA Sambashivan S.;
RT "Structural and Mechanistic Regulation of the Pro-degenerative NAD
RT Hydrolase SARM1.";
RL Cell Rep. 32:107999-107999(2020).
RN [23]
RP STRUCTURE BY ELECTRON MICROSCOPY (2.60 ANGSTROMS) OF MUTANT ALA-642 IN
RP COMPLEX WITH NAD, FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION,
RP DOMAIN, SUBUNIT, AND MUTAGENESIS OF TRP-103; ARG-110; GLN-150; ARG-157;
RP HIS-190; LYS-193; ARG-249; TRP-253; PHE-259; LYS-261 AND GLU-642.
RX PubMed=33053563; DOI=10.1038/s41586-020-2862-z;
RA Jiang Y., Liu T., Lee C.H., Chang Q., Yang J., Zhang Z.;
RT "The NAD+-mediated self-inhibition mechanism of pro-neurodegenerative
RT Sarm1.";
RL Nature 588:658-663(2020).
CC -!- FUNCTION: NAD(+) hydrolase, which plays a key role in axonal
CC degeneration following injury by regulating NAD(+) metabolism
CC (PubMed:25908823, PubMed:27671644, PubMed:28334607). Acts as a negative
CC regulator of MYD88- and TRIF-dependent toll-like receptor signaling
CC pathway by promoting Wallerian degeneration, an injury-induced form of
CC programmed subcellular death which involves degeneration of an axon
CC distal to the injury site (PubMed:15123841, PubMed:16964262,
CC PubMed:20306472, PubMed:25908823). Wallerian degeneration is triggered
CC by NAD(+) depletion: in response to injury, SARM1 is activated and
CC catalyzes cleavage of NAD(+) into ADP-D-ribose (ADPR), cyclic ADPR
CC (cADPR) and nicotinamide; NAD(+) cleavage promoting cytoskeletal
CC degradation and axon destruction (PubMed:25908823, PubMed:28334607,
CC PubMed:30333228, PubMed:31128467, PubMed:31439793, PubMed:32049506,
CC PubMed:32828421, PubMed:31439792, PubMed:33053563). Also able to
CC hydrolyze NADP(+), but not other NAD(+)-related molecules
CC (PubMed:29395922). Can activate neuronal cell death in response to
CC stress (PubMed:20306472). Regulates dendritic arborization through the
CC MAPK4-JNK pathway (By similarity). Involved in innate immune response:
CC inhibits both TICAM1/TRIF- and MYD88-dependent activation of JUN/AP-1,
CC TRIF-dependent activation of NF-kappa-B and IRF3, and the
CC phosphorylation of MAPK14/p38 (PubMed:16964262).
CC {ECO:0000250|UniProtKB:Q6PDS3, ECO:0000269|PubMed:15123841,
CC ECO:0000269|PubMed:16964262, ECO:0000269|PubMed:20306472,
CC ECO:0000269|PubMed:25908823, ECO:0000269|PubMed:27671644,
CC ECO:0000269|PubMed:28334607, ECO:0000269|PubMed:29395922,
CC ECO:0000269|PubMed:30333228, ECO:0000269|PubMed:31128467,
CC ECO:0000269|PubMed:31439792, ECO:0000269|PubMed:31439793,
CC ECO:0000269|PubMed:32049506, ECO:0000269|PubMed:32828421,
CC ECO:0000269|PubMed:33053563}.
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, ECO:0000269|PubMed:30333228,
CC ECO:0000269|PubMed:31128467, ECO:0000269|PubMed:31439792,
CC ECO:0000269|PubMed:31439793, ECO:0000269|PubMed:32049506,
CC ECO:0000269|PubMed:32828421, ECO:0000269|PubMed:33053563};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16302;
CC Evidence={ECO:0000269|PubMed:28334607, ECO:0000269|PubMed:30333228,
CC ECO:0000269|PubMed:31128467, ECO:0000269|PubMed:31439792,
CC ECO:0000269|PubMed:31439793, ECO:0000269|PubMed:32049506,
CC ECO:0000269|PubMed:32828421, ECO:0000269|PubMed:33053563};
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:0000269|PubMed:28334607, ECO:0000269|PubMed:31128467};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38612;
CC Evidence={ECO:0000269|PubMed:28334607, ECO:0000269|PubMed:31128467};
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:0000269|PubMed:29395922};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19850;
CC Evidence={ECO:0000269|PubMed:29395922};
CC -!- ACTIVITY REGULATION: Autoinhibited: in the inactive state, the
CC enzymatic TIR domain is held apart by the autoinhibiting ARM repeats
CC (PubMed:27671644, PubMed:31278906, PubMed:32755591, PubMed:33053563).
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 (PubMed:33053563).
CC Following activation, possibly by nicotinamide mononucleotide (NMN),
CC auto-inhibitory interactions are released, allowing self-association of
CC the TIR domains and subsequent activation of the NAD(+) hydrolase
CC (NADase) activity (PubMed:27671644, PubMed:31128467, PubMed:32755591).
CC Self-association of TIR domains is facilitated by the octamer of SAM
CC domains (PubMed:31278906, PubMed:31439792). NAD(+) hydrolase activity
CC is inhibited by nicotinamide (PubMed:28334607). Specifically inhibited
CC by berberine chloride and zinc chloride (PubMed:32828421).
CC {ECO:0000269|PubMed:27671644, ECO:0000269|PubMed:28334607,
CC ECO:0000269|PubMed:31128467, ECO:0000269|PubMed:31278906,
CC ECO:0000269|PubMed:31439792, ECO:0000269|PubMed:32755591,
CC ECO:0000269|PubMed:32828421, ECO:0000269|PubMed:33053563}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=24 uM for NAD(+) {ECO:0000269|PubMed:28334607};
CC Note=kcat is 10.3 min(-1) with NAD(+) as substrate.
CC {ECO:0000269|PubMed:28334607};
CC -!- SUBUNIT: Homooctamer; forms an octomeric ring via SAM domains
CC (PubMed:31278906, PubMed:31439792, PubMed:32755591, PubMed:33053563).
CC Interacts with TICAM1/TRIF and thereby interferes with TICAM1/TRIF
CC function (PubMed:16964262). Interacts with MAPK10/JNK3 and SDC2 (via
CC cytoplasmic domain) (By similarity). {ECO:0000250|UniProtKB:Q6PDS3,
CC ECO:0000269|PubMed:16964262, ECO:0000269|PubMed:31278906,
CC ECO:0000269|PubMed:31439792, ECO:0000269|PubMed:32755591,
CC ECO:0000269|PubMed:33053563}.
CC -!- INTERACTION:
CC Q6SZW1; Q99836: MYD88; NbExp=5; IntAct=EBI-11693532, EBI-447677;
CC Q6SZW1; Q86XR7: TICAM2; NbExp=2; IntAct=EBI-11693532, EBI-525927;
CC Q6SZW1-1; Q6SZW1-1: SARM1; NbExp=3; IntAct=EBI-22054385, EBI-22054385;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:20306472}. Cell
CC projection, axon {ECO:0000250|UniProtKB:Q6PDS3}. Cell projection,
CC dendrite {ECO:0000250|UniProtKB:Q6PDS3}. Synapse
CC {ECO:0000250|UniProtKB:Q6PDS3}. Mitochondrion
CC {ECO:0000269|PubMed:20306472, ECO:0000269|PubMed:22145856}.
CC Note=Associated with microtubules. {ECO:0000250|UniProtKB:Q6PDS3}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q6SZW1-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q6SZW1-2; Sequence=VSP_013603;
CC -!- TISSUE SPECIFICITY: Predominantly expressed in brain, kidney and liver.
CC Expressed at lower level in placenta. {ECO:0000269|PubMed:11386760,
CC ECO:0000269|PubMed:17724133}.
CC -!- INDUCTION: Up-regulated by lipopolysaccharides (LPS).
CC {ECO:0000269|PubMed:20306472}.
CC -!- DOMAIN: The TIR domain mediates NAD(+) hydrolase (NADase) activity
CC (PubMed:28334607). Self-association of TIR domains is required for
CC NADase activity (PubMed:27671644, PubMed:31278906).
CC {ECO:0000269|PubMed:27671644, ECO:0000269|PubMed:28334607,
CC ECO:0000269|PubMed:31278906}.
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
CC (PubMed:33053563). In contrast to classical ARM repeats, the last helix
CC of ARM 6 does not fold back to interact with the first two helices, but
CC instead turns towards the N-terminus of SARM1 (PubMed:33053563). As a
CC result, the two following motifs ARM 7 and ARM 8 reverse their
CC directions and lie perpendicularly (PubMed:33053563). Moreover, ARM
CC repeats interact with different domains not only within each protomer
CC but also of the adjacent ones (PubMed:33053563).
CC {ECO:0000269|PubMed:33053563}.
CC -!- PTM: Phosphorylation at Ser-548 by JNK kinases (MAPK8, MAPK9 and /or
CC MAPK10) enhance the NAD(+) hydrolase (NADase) activity
CC (PubMed:30333228). Phosphorylation at Ser-548 and subsequent activation
CC takes place in response to oxidative stress conditions and inhibits
CC mitochondrial respiration (PubMed:30333228).
CC {ECO:0000269|PubMed:30333228}.
CC -!- SIMILARITY: Belongs to the SARM1 family. {ECO:0000305}.
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DR EMBL; AJ290445; CAB90355.1; -; mRNA.
DR EMBL; AY444166; AAR17520.1; -; mRNA.
DR EMBL; AB011096; BAA25450.1; -; mRNA.
DR CCDS; CCDS11230.2; -. [Q6SZW1-1]
DR RefSeq; NP_055892.2; NM_015077.3. [Q6SZW1-1]
DR PDB; 6O0Q; X-ray; 1.80 A; A/B=560-700.
DR PDB; 6O0R; X-ray; 1.80 A; A/B=560-700.
DR PDB; 6O0S; X-ray; 2.70 A; A/B/C/D/E/F/G/H=409-561.
DR PDB; 6O0T; X-ray; 2.80 A; A/B/C/D/E/F/G/H=409-561.
DR PDB; 6O0U; X-ray; 3.03 A; A/B=560-700.
DR PDB; 6O0V; X-ray; 2.07 A; A/B/C/D=560-700.
DR PDB; 6O1B; X-ray; 1.67 A; A=560-700.
DR PDB; 6QWV; X-ray; 2.47 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P=387-548.
DR PDB; 6WPK; EM; 3.30 A; A/B/C/D/E/F/G/H=49-724.
DR PDB; 6ZFX; EM; 2.88 A; A/B/C/D/E/F/G/H=26-724.
DR PDB; 6ZG0; EM; 7.70 A; A/B/C/D/E/F/G/H=26-724.
DR PDB; 6ZG1; EM; 3.77 A; A/B/C/D/E/F/G/H=387-548.
DR PDB; 7ANW; EM; 2.68 A; A/B/C/D/E/F/G/H=26-724.
DR PDB; 7CM5; EM; 2.60 A; A/B/C/D/E/F/G/H=1-724.
DR PDB; 7CM6; EM; 3.00 A; A/B/C/D/E/F/G/H=1-724.
DR PDB; 7CM7; EM; 2.60 A; A/B/C/D/E/F/G/H=1-724.
DR PDB; 7DJT; EM; 2.80 A; A/B/C/D/E/F/G/H=27-724.
DR PDB; 7KNQ; EM; 3.40 A; A/B/C/D/E/F/G/H=1-724.
DR PDB; 7LD0; EM; 3.10 A; A/B/C/D/E/F/G/H=28-724.
DR PDB; 7NAG; X-ray; 1.72 A; A/B=560-700.
DR PDB; 7NAH; X-ray; 1.79 A; A/B=560-700.
DR PDB; 7NAI; X-ray; 1.74 A; A/B=560-700.
DR PDB; 7NAJ; X-ray; 1.60 A; A/B=560-700.
DR PDB; 7NAK; EM; 2.90 A; A/B/C/D/E/F/G/H=28-724.
DR PDB; 7NAL; EM; 3.00 A; A/B/C/D/E/F/G/H=28-724.
DR PDBsum; 6O0Q; -.
DR PDBsum; 6O0R; -.
DR PDBsum; 6O0S; -.
DR PDBsum; 6O0T; -.
DR PDBsum; 6O0U; -.
DR PDBsum; 6O0V; -.
DR PDBsum; 6O1B; -.
DR PDBsum; 6QWV; -.
DR PDBsum; 6WPK; -.
DR PDBsum; 6ZFX; -.
DR PDBsum; 6ZG0; -.
DR PDBsum; 6ZG1; -.
DR PDBsum; 7ANW; -.
DR PDBsum; 7CM5; -.
DR PDBsum; 7CM6; -.
DR PDBsum; 7CM7; -.
DR PDBsum; 7DJT; -.
DR PDBsum; 7KNQ; -.
DR PDBsum; 7LD0; -.
DR PDBsum; 7NAG; -.
DR PDBsum; 7NAH; -.
DR PDBsum; 7NAI; -.
DR PDBsum; 7NAJ; -.
DR PDBsum; 7NAK; -.
DR PDBsum; 7NAL; -.
DR AlphaFoldDB; Q6SZW1; -.
DR SMR; Q6SZW1; -.
DR BioGRID; 116726; 45.
DR IntAct; Q6SZW1; 16.
DR STRING; 9606.ENSP00000468032; -.
DR BindingDB; Q6SZW1; -.
DR ChEMBL; CHEMBL4523350; -.
DR iPTMnet; Q6SZW1; -.
DR PhosphoSitePlus; Q6SZW1; -.
DR BioMuta; SARM1; -.
DR DMDM; 83288284; -.
DR EPD; Q6SZW1; -.
DR jPOST; Q6SZW1; -.
DR MassIVE; Q6SZW1; -.
DR MaxQB; Q6SZW1; -.
DR PaxDb; Q6SZW1; -.
DR PeptideAtlas; Q6SZW1; -.
DR PRIDE; Q6SZW1; -.
DR ProteomicsDB; 67362; -. [Q6SZW1-1]
DR ProteomicsDB; 67363; -. [Q6SZW1-2]
DR Antibodypedia; 14061; 208 antibodies from 34 providers.
DR DNASU; 23098; -.
DR Ensembl; ENST00000585482.6; ENSP00000468032.2; ENSG00000004139.14. [Q6SZW1-1]
DR GeneID; 23098; -.
DR KEGG; hsa:23098; -.
DR MANE-Select; ENST00000585482.6; ENSP00000468032.2; NM_015077.4; NP_055892.2.
DR UCSC; uc032ezg.2; human. [Q6SZW1-1]
DR CTD; 23098; -.
DR DisGeNET; 23098; -.
DR GeneCards; SARM1; -.
DR HGNC; HGNC:17074; SARM1.
DR HPA; ENSG00000004139; Low tissue specificity.
DR MalaCards; SARM1; -.
DR MIM; 607732; gene.
DR neXtProt; NX_Q6SZW1; -.
DR OpenTargets; ENSG00000004139; -.
DR PharmGKB; PA134971180; -.
DR VEuPathDB; HostDB:ENSG00000004139; -.
DR eggNOG; KOG3678; Eukaryota.
DR GeneTree; ENSGT00390000004155; -.
DR HOGENOM; CLU_003286_2_0_1; -.
DR InParanoid; Q6SZW1; -.
DR OMA; CVPSWKE; -.
DR PhylomeDB; Q6SZW1; -.
DR PathwayCommons; Q6SZW1; -.
DR Reactome; R-HSA-166166; MyD88-independent TLR4 cascade. [Q6SZW1-1]
DR Reactome; R-HSA-168164; Toll Like Receptor 3 (TLR3) Cascade. [Q6SZW1-1]
DR Reactome; R-HSA-936964; Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon. [Q6SZW1-1]
DR Reactome; R-HSA-937041; IKK complex recruitment mediated by RIP1. [Q6SZW1-1]
DR Reactome; R-HSA-937072; TRAF6-mediated induction of TAK1 complex within TLR4 complex. [Q6SZW1-1]
DR SignaLink; Q6SZW1; -.
DR SIGNOR; Q6SZW1; -.
DR BioGRID-ORCS; 23098; 6 hits in 234 CRISPR screens.
DR ChiTaRS; SARM1; human.
DR GenomeRNAi; 23098; -.
DR Pharos; Q6SZW1; Tchem.
DR PRO; PR:Q6SZW1; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; Q6SZW1; protein.
DR Bgee; ENSG00000004139; Expressed in body of pancreas and 139 other tissues.
DR ExpressionAtlas; Q6SZW1; baseline and differential.
DR Genevisible; Q6SZW1; HS.
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; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0030425; C:dendrite; ISS:UniProtKB.
DR GO; GO:0031315; C:extrinsic component of mitochondrial outer membrane; IEA:Ensembl.
DR GO; GO:0005874; C:microtubule; ISS:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0045202; C:synapse; ISS:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
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; IDA: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; IDA:UniProtKB.
DR GO; GO:0048814; P:regulation of dendrite morphogenesis; ISS:UniProtKB.
DR GO; GO:0043523; P:regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:1901214; P:regulation of neuron death; ISS:UniProtKB.
DR GO; GO:0048678; P:response to axon injury; IDA:UniProtKB.
DR GO; GO:0009749; P:response to glucose; IEA:Ensembl.
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 3D-structure; Alternative splicing; Cell projection; Cytoplasm;
KW Differentiation; Hydrolase; Immunity; Innate immunity; Mitochondrion; NAD;
KW Neurogenesis; Phosphoprotein; Reference proteome; Repeat; Synapse;
KW Transit peptide.
FT TRANSIT 1..27
FT /note="Mitochondrion"
FT /evidence="ECO:0000269|PubMed:22145856"
FT CHAIN 28..724
FT /note="NAD(+) hydrolase SARM1"
FT /id="PRO_0000097589"
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 704..724
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 642
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204,
FT ECO:0000305|PubMed:28334607, ECO:0000305|PubMed:31439792,
FT ECO:0000305|PubMed:31439793"
FT BINDING 103
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /ligand_label="1"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000269|PubMed:33053563,
FT ECO:0007744|PDB:7CM6, ECO:0007744|PDB:7CM7"
FT BINDING 110
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /ligand_label="1"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000269|PubMed:33053563,
FT ECO:0007744|PDB:7CM6, ECO:0007744|PDB:7CM7"
FT BINDING 149..157
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /ligand_label="1"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000269|PubMed:33053563,
FT ECO:0007744|PDB:7CM6, ECO:0007744|PDB:7CM7"
FT BINDING 190..193
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /ligand_label="1"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000269|PubMed:33053563,
FT ECO:0007744|PDB:7CM6, ECO:0007744|PDB:7CM7"
FT BINDING 569..570
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /ligand_label="2"
FT /ligand_note="substrate"
FT /evidence="ECO:0000305|PubMed:31439792"
FT BINDING 599
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /ligand_label="2"
FT /ligand_note="substrate"
FT /evidence="ECO:0000305|PubMed:31439792"
FT MOD_RES 548
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:30333228"
FT MOD_RES 558
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q6PDS3"
FT VAR_SEQ 1..106
FT /note="MVLTLLLSAYKLCRFFAMSGPRPGAERLAVPGPDGGGGTGPWWAAGGRGPRE
FT VSPGAGTEVQDALERALPELQQALSALKQAGGARAVGAGLAEVFQLVEEAWLLP -> M
FT GAVARAHGGLRVARARESVAGGRHRGAGRPGARAAGAAAGLVRAEAGGRRAGRGRRPGR
FT GLPTGGGGLAAA (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11386760"
FT /id="VSP_013603"
FT VARIANT 23
FT /note="P -> R (in dbSNP:rs7212814)"
FT /id="VAR_061702"
FT MUTAGEN 11
FT /note="K->A: No effect on mitochondrial localization."
FT /evidence="ECO:0000269|PubMed:22145856"
FT MUTAGEN 14
FT /note="R->A: Loss in ability to localize to mitochondria
FT and reduction in apoptotic activity."
FT /evidence="ECO:0000269|PubMed:22145856"
FT MUTAGEN 22
FT /note="R->A: No effect on mitochondrial localization."
FT /evidence="ECO:0000269|PubMed:22145856"
FT MUTAGEN 27
FT /note="R->A: No effect on mitochondrial localization."
FT /evidence="ECO:0000269|PubMed:22145856"
FT MUTAGEN 103
FT /note="W->A: In WQH to A mutant: Increased NAD(+)-binding
FT to ARM repeats, leading to decreased NAD(+) hydrolase
FT activity; when associated with A-150 and A-190."
FT /evidence="ECO:0000269|PubMed:33053563"
FT MUTAGEN 110
FT /note="R->A: In RRK to A mutant: Slightly reduced NAD(+)-
FT binding to ARM repeats; when associated with A-157 and A-
FT 193."
FT /evidence="ECO:0000269|PubMed:33053563"
FT MUTAGEN 110
FT /note="R->E: In RRK to E mutant: Strongly reduced NAD(+)-
FT binding to ARM repeats, leading to enhanced NAD(+)
FT hydrolase activity and constitutive axonal degeneration in
FT absence of injury; when associated with E-157 and A-193."
FT /evidence="ECO:0000269|PubMed:33053563"
FT MUTAGEN 150
FT /note="Q->A: In WQH to A mutant: Increased NAD(+)-binding
FT to ARM repeats, leading to decreased NAD(+) hydrolase
FT activity; when associated with A-103 and A-190."
FT /evidence="ECO:0000269|PubMed:33053563"
FT MUTAGEN 157
FT /note="R->A: In RRK to A mutant: Slightly reduced NAD(+)-
FT binding to ARM repeats; when associated with A-110 and A-
FT 193."
FT /evidence="ECO:0000269|PubMed:33053563"
FT MUTAGEN 157
FT /note="R->E: In RRK to E mutant: Strongly reduced NAD(+)-
FT binding to ARM repeats, leading to enhanced NAD(+)
FT hydrolase activity and constitutive axonal degeneration in
FT absence of injury; when associated with E-110 and A-193."
FT /evidence="ECO:0000269|PubMed:33053563"
FT MUTAGEN 190
FT /note="H->A: In WQH to A mutant: Increased NAD(+)-binding
FT to ARM repeats, leading to decreased NAD(+) hydrolase
FT activity; when associated with A-103 and A-150."
FT /evidence="ECO:0000269|PubMed:33053563"
FT MUTAGEN 193
FT /note="K->A: In RRK to A mutant: Slightly reduced NAD(+)-
FT binding to ARM repeats; when associated with A-110 and A-
FT 157."
FT /evidence="ECO:0000269|PubMed:33053563"
FT MUTAGEN 193
FT /note="K->E: In RRK to E mutant: Strongly reduced NAD(+)-
FT binding to ARM repeats, leading to enhanced NAD(+)
FT hydrolase activity and constitutive axonal degeneration in
FT absence of injury; when associated with E-110 and E-157."
FT /evidence="ECO:0000269|PubMed:33053563"
FT MUTAGEN 249
FT /note="R->A: No effect on octamer formation; does not
FT affect NAD(+) hydrolase activity."
FT /evidence="ECO:0000269|PubMed:33053563"
FT MUTAGEN 253
FT /note="W->A: Constitutively active mutant; strong ability
FT to trigger axonal degeneration caused by disrupted
FT interaction between the TIR domain and ARM repeats."
FT /evidence="ECO:0000269|PubMed:33053563"
FT MUTAGEN 259
FT /note="F->A: No effect on octamer formation. Shows
FT increased NAD(+) hydrolase activity and ability to trigger
FT axonal degeneration."
FT /evidence="ECO:0000269|PubMed:33053563"
FT MUTAGEN 261
FT /note="K->A: No effect on octamer formation; does not
FT affect NAD(+) hydrolase activity."
FT /evidence="ECO:0000269|PubMed:33053563"
FT MUTAGEN 408
FT /note="S->A: Does not affect phosphorylation level."
FT /evidence="ECO:0000269|PubMed:30333228"
FT MUTAGEN 411
FT /note="S->A: Does not affect phosphorylation level."
FT /evidence="ECO:0000269|PubMed:30333228"
FT MUTAGEN 419
FT /note="T->A: Does not affect phosphorylation level."
FT /evidence="ECO:0000269|PubMed:30333228"
FT MUTAGEN 427
FT /note="S->A: Does not affect phosphorylation level."
FT /evidence="ECO:0000269|PubMed:30333228"
FT MUTAGEN 432
FT /note="S->A: Does not affect phosphorylation level."
FT /evidence="ECO:0000269|PubMed:30333228"
FT MUTAGEN 447
FT /note="T->A: Does not affect phosphorylation level."
FT /evidence="ECO:0000269|PubMed:30333228"
FT MUTAGEN 453
FT /note="T->A: Does not affect phosphorylation level."
FT /evidence="ECO:0000269|PubMed:30333228"
FT MUTAGEN 454
FT /note="D->K: Reduced ability to form an octomeric ring and
FT promote axonal degeneration following injury."
FT /evidence="ECO:0000269|PubMed:31278906"
FT MUTAGEN 461..464
FT /note="ITRK->DTRD: Strongly reduced ability to form an
FT octomeric ring and promote axonal degeneration following
FT injury."
FT /evidence="ECO:0000269|PubMed:31278906"
FT MUTAGEN 461
FT /note="I->D: Reduced ability to form an octomeric ring and
FT promote axonal degeneration following injury."
FT /evidence="ECO:0000269|PubMed:31278906"
FT MUTAGEN 462
FT /note="T->A: Does not affect phosphorylation level."
FT /evidence="ECO:0000269|PubMed:30333228"
FT MUTAGEN 464
FT /note="K->D: Reduced ability to form an octomeric ring and
FT promote axonal degeneration following injury."
FT /evidence="ECO:0000269|PubMed:31278906"
FT MUTAGEN 471
FT /note="T->A: Does not affect phosphorylation level."
FT /evidence="ECO:0000269|PubMed:30333228"
FT MUTAGEN 475
FT /note="T->A: Does not affect phosphorylation level."
FT /evidence="ECO:0000269|PubMed:30333228"
FT MUTAGEN 480
FT /note="S->A: Does not affect phosphorylation level."
FT /evidence="ECO:0000269|PubMed:30333228"
FT MUTAGEN 481
FT /note="T->A: Does not affect phosphorylation level."
FT /evidence="ECO:0000269|PubMed:30333228"
FT MUTAGEN 485
FT /note="S->A: Does not affect phosphorylation level."
FT /evidence="ECO:0000269|PubMed:30333228"
FT MUTAGEN 493
FT /note="S->A: Does not affect phosphorylation level."
FT /evidence="ECO:0000269|PubMed:30333228"
FT MUTAGEN 502
FT /note="T->A: Does not affect phosphorylation level."
FT /evidence="ECO:0000269|PubMed:30333228"
FT MUTAGEN 507
FT /note="S->A: Does not affect phosphorylation level."
FT /evidence="ECO:0000269|PubMed:30333228"
FT MUTAGEN 513
FT /note="S->A: Does not affect phosphorylation level."
FT /evidence="ECO:0000269|PubMed:30333228"
FT MUTAGEN 519
FT /note="S->A: Does not affect phosphorylation level."
FT /evidence="ECO:0000269|PubMed:30333228"
FT MUTAGEN 531..533
FT /note="LGV->DGD: Slightly reduced ability to form an
FT octomeric ring and promote axonal degeneration following
FT injury."
FT /evidence="ECO:0000269|PubMed:31278906"
FT MUTAGEN 531
FT /note="L->D: Slightly reduced ability to form an octomeric
FT ring and promote axonal degeneration following injury."
FT /evidence="ECO:0000269|PubMed:31278906"
FT MUTAGEN 533
FT /note="V->D: Slightly reduced ability to form an octomeric
FT ring and promote axonal degeneration following injury."
FT /evidence="ECO:0000269|PubMed:31278906"
FT MUTAGEN 540
FT /note="T->A: Does not affect phosphorylation level."
FT /evidence="ECO:0000269|PubMed:30333228"
FT MUTAGEN 548
FT /note="S->A: Decreased phosphorylation, leading to reduced
FT NAD(+) hydrolase activity."
FT /evidence="ECO:0000269|PubMed:30333228"
FT MUTAGEN 568
FT /note="Y->A: Loss of NAD(+) hydrolase activity."
FT /evidence="ECO:0000269|PubMed:31439792"
FT MUTAGEN 569..570
FT /note="RR->AA: Loss of NAD(+) hydrolase activity."
FT /evidence="ECO:0000269|PubMed:31439792"
FT MUTAGEN 569
FT /note="R->A: Loss of NAD(+) hydrolase activity."
FT /evidence="ECO:0000269|PubMed:31439792"
FT MUTAGEN 579
FT /note="L->A: Reduced NAD(+) hydrolase activity."
FT /evidence="ECO:0000269|PubMed:31439792"
FT MUTAGEN 594
FT /note="D->A: Reduced NAD(+) hydrolase activity."
FT /evidence="ECO:0000269|PubMed:31439792"
FT MUTAGEN 596
FT /note="E->K: Loss of NAD(+) hydrolase activity. Abolished
FT ability to promote axonal degeneration following injury."
FT /evidence="ECO:0000269|PubMed:27671644,
FT ECO:0000269|PubMed:28334607, ECO:0000269|PubMed:31439792"
FT MUTAGEN 597
FT /note="K->E: Dominant negative mutant that blocks axon
FT degeneration after axotomy."
FT /evidence="ECO:0000269|PubMed:27671644"
FT MUTAGEN 601
FT /note="G->P: Loss of NAD(+) hydrolase activity. Abolished
FT ability to promote axonal degeneration following injury."
FT /evidence="ECO:0000269|PubMed:27671644,
FT ECO:0000269|PubMed:28334607, ECO:0000269|PubMed:31439792"
FT MUTAGEN 604
FT /note="E->K: Does not affect ability to promote axonal
FT degeneration following injury."
FT /evidence="ECO:0000269|PubMed:27671644"
FT MUTAGEN 626
FT /note="L->M: Does not affect ability to promote axonal
FT degeneration following injury."
FT /evidence="ECO:0000269|PubMed:27671644"
FT MUTAGEN 627
FT /note="D->K: Abolished ability to promote axonal
FT degeneration following injury."
FT /evidence="ECO:0000269|PubMed:27671644"
FT MUTAGEN 628
FT /note="K->D: Abolished ability to promote axonal
FT degeneration following injury."
FT /evidence="ECO:0000269|PubMed:27671644"
FT MUTAGEN 629
FT /note="C->A: Abolished NAD(+) hydrolase activity."
FT /evidence="ECO:0000269|PubMed:32828421"
FT MUTAGEN 629
FT /note="C->S: Abolished ability to promote axonal
FT degeneration following injury."
FT /evidence="ECO:0000269|PubMed:27671644"
FT MUTAGEN 632
FT /note="D->K: Does not affect ability to promote axonal
FT degeneration following injury."
FT /evidence="ECO:0000269|PubMed:27671644"
FT MUTAGEN 635
FT /note="C->A: Abolished NAD(+) hydrolase activity."
FT /evidence="ECO:0000269|PubMed:32828421"
FT MUTAGEN 642
FT /note="E->K: Loss of NAD(+) hydrolase activity."
FT /evidence="ECO:0000269|PubMed:28334607,
FT ECO:0000269|PubMed:31128467, ECO:0000269|PubMed:31439792,
FT ECO:0000269|PubMed:31439793, ECO:0000269|PubMed:33053563"
FT MUTAGEN 685
FT /note="H->A: Reduced NAD(+) hydrolase activity."
FT /evidence="ECO:0000269|PubMed:31439792"
FT HELIX 63..81
FT /evidence="ECO:0007829|PDB:7CM5"
FT HELIX 86..103
FT /evidence="ECO:0007829|PDB:7CM5"
FT STRAND 106..108
FT /evidence="ECO:0007829|PDB:7ANW"
FT HELIX 109..122
FT /evidence="ECO:0007829|PDB:7CM5"
FT HELIX 125..132
FT /evidence="ECO:0007829|PDB:7CM5"
FT HELIX 139..151
FT /evidence="ECO:0007829|PDB:7CM5"
FT HELIX 156..162
FT /evidence="ECO:0007829|PDB:7CM5"
FT TURN 163..166
FT /evidence="ECO:0007829|PDB:7CM5"
FT HELIX 167..171
FT /evidence="ECO:0007829|PDB:7CM5"
FT HELIX 178..191
FT /evidence="ECO:0007829|PDB:7CM5"
FT HELIX 196..204
FT /evidence="ECO:0007829|PDB:7CM5"
FT TURN 205..207
FT /evidence="ECO:0007829|PDB:7CM5"
FT HELIX 208..214
FT /evidence="ECO:0007829|PDB:7CM5"
FT HELIX 222..235
FT /evidence="ECO:0007829|PDB:7CM5"
FT HELIX 239..247
FT /evidence="ECO:0007829|PDB:7CM5"
FT TURN 248..254
FT /evidence="ECO:0007829|PDB:7CM5"
FT HELIX 255..259
FT /evidence="ECO:0007829|PDB:7CM5"
FT HELIX 265..278
FT /evidence="ECO:0007829|PDB:7CM5"
FT TURN 281..283
FT /evidence="ECO:0007829|PDB:7CM5"
FT HELIX 284..290
FT /evidence="ECO:0007829|PDB:7CM5"
FT TURN 291..295
FT /evidence="ECO:0007829|PDB:7CM7"
FT HELIX 296..302
FT /evidence="ECO:0007829|PDB:7CM5"
FT HELIX 305..308
FT /evidence="ECO:0007829|PDB:7CM5"
FT TURN 309..311
FT /evidence="ECO:0007829|PDB:7CM5"
FT STRAND 313..316
FT /evidence="ECO:0007829|PDB:7ANW"
FT TURN 317..320
FT /evidence="ECO:0007829|PDB:7ANW"
FT HELIX 324..327
FT /evidence="ECO:0007829|PDB:7CM5"
FT TURN 328..330
FT /evidence="ECO:0007829|PDB:7CM5"
FT TURN 332..334
FT /evidence="ECO:0007829|PDB:7CM5"
FT STRAND 335..337
FT /evidence="ECO:0007829|PDB:7DJT"
FT HELIX 339..358
FT /evidence="ECO:0007829|PDB:7CM5"
FT HELIX 363..368
FT /evidence="ECO:0007829|PDB:7CM5"
FT HELIX 370..379
FT /evidence="ECO:0007829|PDB:7CM5"
FT HELIX 395..397
FT /evidence="ECO:0007829|PDB:6QWV"
FT STRAND 398..401
FT /evidence="ECO:0007829|PDB:6QWV"
FT HELIX 409..411
FT /evidence="ECO:0007829|PDB:6QWV"
FT HELIX 414..423
FT /evidence="ECO:0007829|PDB:6QWV"
FT HELIX 427..429
FT /evidence="ECO:0007829|PDB:6QWV"
FT HELIX 430..435
FT /evidence="ECO:0007829|PDB:6QWV"
FT HELIX 440..444
FT /evidence="ECO:0007829|PDB:6QWV"
FT HELIX 448..453
FT /evidence="ECO:0007829|PDB:6QWV"
FT HELIX 460..475
FT /evidence="ECO:0007829|PDB:6QWV"
FT TURN 480..482
FT /evidence="ECO:0007829|PDB:6QWV"
FT HELIX 487..494
FT /evidence="ECO:0007829|PDB:6QWV"
FT HELIX 496..501
FT /evidence="ECO:0007829|PDB:6QWV"
FT HELIX 502..507
FT /evidence="ECO:0007829|PDB:6QWV"
FT HELIX 512..515
FT /evidence="ECO:0007829|PDB:6QWV"
FT HELIX 520..525
FT /evidence="ECO:0007829|PDB:6QWV"
FT HELIX 532..543
FT /evidence="ECO:0007829|PDB:6QWV"
FT STRAND 564..567
FT /evidence="ECO:0007829|PDB:6O1B"
FT HELIX 570..586
FT /evidence="ECO:0007829|PDB:6O1B"
FT STRAND 591..593
FT /evidence="ECO:0007829|PDB:6O0V"
FT HELIX 596..598
FT /evidence="ECO:0007829|PDB:6O1B"
FT HELIX 601..603
FT /evidence="ECO:0007829|PDB:6O1B"
FT HELIX 604..613
FT /evidence="ECO:0007829|PDB:6O1B"
FT STRAND 615..621
FT /evidence="ECO:0007829|PDB:6O1B"
FT TURN 623..626
FT /evidence="ECO:0007829|PDB:6O1B"
FT HELIX 627..629
FT /evidence="ECO:0007829|PDB:6O1B"
FT STRAND 634..637
FT /evidence="ECO:0007829|PDB:7DJT"
FT HELIX 638..648
FT /evidence="ECO:0007829|PDB:6O1B"
FT STRAND 652..659
FT /evidence="ECO:0007829|PDB:6O1B"
FT HELIX 665..667
FT /evidence="ECO:0007829|PDB:6O1B"
FT HELIX 670..677
FT /evidence="ECO:0007829|PDB:6O1B"
FT STRAND 685..687
FT /evidence="ECO:0007829|PDB:7CM5"
FT HELIX 688..698
FT /evidence="ECO:0007829|PDB:6O1B"
FT HELIX 701..703
FT /evidence="ECO:0007829|PDB:7DJT"
SQ SEQUENCE 724 AA; 79388 MW; 6391EA4C31EF6604 CRC64;
MVLTLLLSAY KLCRFFAMSG PRPGAERLAV PGPDGGGGTG PWWAAGGRGP REVSPGAGTE
VQDALERALP ELQQALSALK QAGGARAVGA GLAEVFQLVE EAWLLPAVGR EVAQGLCDAI
RLDGGLDLLL RLLQAPELET RVQAARLLEQ ILVAENRDRV ARIGLGVILN LAKEREPVEL
ARSVAGILEH MFKHSEETCQ RLVAAGGLDA VLYWCRRTDP ALLRHCALAL GNCALHGGQA
VQRRMVEKRA AEWLFPLAFS KEDELLRLHA CLAVAVLATN KEVEREVERS GTLALVEPLV
ASLDPGRFAR CLVDASDTSQ GRGPDDLQRL VPLLDSNRLE AQCIGAFYLC AEAAIKSLQG
KTKVFSDIGA IQSLKRLVSY STNGTKSALA KRALRLLGEE VPRPILPSVP SWKEAEVQTW
LQQIGFSKYC ESFREQQVDG DLLLRLTEEE LQTDLGMKSG ITRKRFFREL TELKTFANYS
TCDRSNLADW LGSLDPRFRQ YTYGLVSCGL DRSLLHRVSE QQLLEDCGIH LGVHRARILT
AAREMLHSPL PCTGGKPSGD TPDVFISYRR NSGSQLASLL KVHLQLHGFS VFIDVEKLEA
GKFEDKLIQS VMGARNFVLV LSPGALDKCM QDHDCKDWVH KEIVTALSCG KNIVPIIDGF
EWPEPQVLPE DMQAVLTFNG IKWSHEYQEA TIEKIIRFLQ GRSSRDSSAG SDTSLEGAAP
MGPT
