SARM1_DANRE
ID SARM1_DANRE Reviewed; 713 AA.
AC F1QWA8; B3DK97; Q6TQG1;
DT 11-DEC-2019, integrated into UniProtKB/Swiss-Prot.
DT 03-MAY-2011, sequence version 1.
DT 03-AUG-2022, entry version 61.
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:0000250|UniProtKB:Q6SZW1};
DE Flags: Precursor;
GN Name=sarm1 {ECO:0000312|ZFIN:ZDB-GENE-040219-1};
OS Danio rerio (Zebrafish) (Brachydanio rerio).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Actinopterygii; Neopterygii; Teleostei; Ostariophysi; Cypriniformes;
OC Danionidae; Danioninae; Danio.
OX NCBI_TaxID=7955;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Tuebingen;
RX PubMed=23594743; DOI=10.1038/nature12111;
RA Howe K., Clark M.D., Torroja C.F., Torrance J., Berthelot C., Muffato M.,
RA Collins J.E., Humphray S., McLaren K., Matthews L., McLaren S., Sealy I.,
RA Caccamo M., Churcher C., Scott C., Barrett J.C., Koch R., Rauch G.J.,
RA White S., Chow W., Kilian B., Quintais L.T., Guerra-Assuncao J.A., Zhou Y.,
RA Gu Y., Yen J., Vogel J.H., Eyre T., Redmond S., Banerjee R., Chi J., Fu B.,
RA Langley E., Maguire S.F., Laird G.K., Lloyd D., Kenyon E., Donaldson S.,
RA Sehra H., Almeida-King J., Loveland J., Trevanion S., Jones M., Quail M.,
RA Willey D., Hunt A., Burton J., Sims S., McLay K., Plumb B., Davis J.,
RA Clee C., Oliver K., Clark R., Riddle C., Elliot D., Threadgold G.,
RA Harden G., Ware D., Begum S., Mortimore B., Kerry G., Heath P.,
RA Phillimore B., Tracey A., Corby N., Dunn M., Johnson C., Wood J., Clark S.,
RA Pelan S., Griffiths G., Smith M., Glithero R., Howden P., Barker N.,
RA Lloyd C., Stevens C., Harley J., Holt K., Panagiotidis G., Lovell J.,
RA Beasley H., Henderson C., Gordon D., Auger K., Wright D., Collins J.,
RA Raisen C., Dyer L., Leung K., Robertson L., Ambridge K., Leongamornlert D.,
RA McGuire S., Gilderthorp R., Griffiths C., Manthravadi D., Nichol S.,
RA Barker G., Whitehead S., Kay M., Brown J., Murnane C., Gray E.,
RA Humphries M., Sycamore N., Barker D., Saunders D., Wallis J., Babbage A.,
RA Hammond S., Mashreghi-Mohammadi M., Barr L., Martin S., Wray P.,
RA Ellington A., Matthews N., Ellwood M., Woodmansey R., Clark G., Cooper J.,
RA Tromans A., Grafham D., Skuce C., Pandian R., Andrews R., Harrison E.,
RA Kimberley A., Garnett J., Fosker N., Hall R., Garner P., Kelly D., Bird C.,
RA Palmer S., Gehring I., Berger A., Dooley C.M., Ersan-Urun Z., Eser C.,
RA Geiger H., Geisler M., Karotki L., Kirn A., Konantz J., Konantz M.,
RA Oberlander M., Rudolph-Geiger S., Teucke M., Lanz C., Raddatz G.,
RA Osoegawa K., Zhu B., Rapp A., Widaa S., Langford C., Yang F.,
RA Schuster S.C., Carter N.P., Harrow J., Ning Z., Herrero J., Searle S.M.,
RA Enright A., Geisler R., Plasterk R.H., Lee C., Westerfield M.,
RA de Jong P.J., Zon L.I., Postlethwait J.H., Nusslein-Volhard C.,
RA Hubbard T.J., Roest Crollius H., Rogers J., Stemple D.L.;
RT "The zebrafish reference genome sequence and its relationship to the human
RT genome.";
RL Nature 496:498-503(2013).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RG NIH - Zebrafish Gene Collection (ZGC) project;
RL Submitted (APR-2008) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 577-682.
RX PubMed=14687934; DOI=10.1016/j.molimm.2003.10.003;
RA Meijer A.H., Krens S.F.G., Medina Rodriguez I.A., He S., Bitter W.,
RA Snaar-Jagalska B.E., Spaink H.P.;
RT "Expression analysis of the Toll-like receptor and TIR domain adaptor
RT families of zebrafish.";
RL Mol. Immunol. 40:773-783(2004).
RN [4]
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 [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=32001778; DOI=10.1038/s42003-020-0776-9;
RA Tian W., Czopka T., Lopez-Schier H.;
RT "Systemic loss of Sarm1 protects Schwann cells from chemotoxicity by
RT delaying axon degeneration.";
RL Commun. Biol. 3:49-49(2020).
RN [6]
RP DISRUPTION PHENOTYPE.
RX PubMed=32728661; DOI=10.17912/micropub.biology.000283;
RA Tian W., Lopez-Schier H.;
RT "Blocking Wallerian degeneration by loss of Sarm1 does not promote axon
RT resealing in zebrafish.";
RL MicroPubl. Biol. 2020:0-0(2020).
CC -!- FUNCTION: NAD(+) hydrolase, which plays a key role in axonal
CC degeneration following injury by regulating NAD(+) metabolism
CC (PubMed:32001778). Acts as a negative regulator of MYD88- and TRIF-
CC dependent toll-like receptor signaling pathway by promoting Wallerian
CC degeneration, an injury-induced form of programmed subcellular death
CC which involves degeneration of an axon distal to the injury site (By
CC similarity). Wallerian degeneration is triggerred by NAD(+) depletion:
CC in response to injury, SARM1 is activated and catalyzes cleavage of
CC NAD(+) into ADP-D-ribose (ADPR), cyclic ADPR (cADPR) and nicotinamide;
CC NAD(+) cleavage 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 (By similarity).
CC {ECO:0000250|UniProtKB:Q6SZW1, ECO:0000269|PubMed:28334607,
CC ECO:0000269|PubMed:32001778}.
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.
CC {ECO:0000250|UniProtKB:Q6SZW1}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q6SZW1}. 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:0000250|UniProtKB:Q6SZW1}. Note=Associated with microtubules.
CC {ECO:0000250|UniProtKB:Q6PDS3}.
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 -!- DISRUPTION PHENOTYPE: Absence of sarm1 provides a level of protection
CC against axon degeneration (PubMed:32001778). Schwann cells are
CC protected from chemotoxicity by delaying axon degeneration
CC (PubMed:32001778). Absence of Sarm1 does not promote axon resealing
CC (PubMed:32728661). {ECO:0000269|PubMed:32001778,
CC ECO:0000269|PubMed:32728661}.
CC -!- SIMILARITY: Belongs to the SARM1 family. {ECO:0000305}.
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DR EMBL; BX663513; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CR522882; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC163770; AAI63770.1; -; mRNA.
DR EMBL; AY389466; AAQ91327.1; -; mRNA.
DR RefSeq; NP_001124068.1; NM_001130596.1.
DR AlphaFoldDB; F1QWA8; -.
DR SMR; F1QWA8; -.
DR STRING; 7955.ENSDARP00000014434; -.
DR PaxDb; F1QWA8; -.
DR Ensembl; ENSDART00000004200; ENSDARP00000014434; ENSDARG00000010610.
DR GeneID; 403143; -.
DR KEGG; dre:403143; -.
DR CTD; 23098; -.
DR ZFIN; ZDB-GENE-040219-1; sarm1.
DR eggNOG; KOG3678; Eukaryota.
DR GeneTree; ENSGT00390000004155; -.
DR HOGENOM; CLU_003286_2_0_1; -.
DR InParanoid; F1QWA8; -.
DR OMA; QHDCHID; -.
DR OrthoDB; 206466at2759; -.
DR PhylomeDB; F1QWA8; -.
DR TreeFam; TF315263; -.
DR PRO; PR:F1QWA8; -.
DR Proteomes; UP000000437; Genome assembly.
DR Proteomes; UP000814640; Chromosome 15.
DR Bgee; ENSDARG00000010610; Expressed in testis and 15 other tissues.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0030424; C:axon; IEA:UniProtKB-SubCell.
DR GO; GO:0030425; C:dendrite; IBA:GO_Central.
DR GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell.
DR GO; GO:0045202; C:synapse; IEA:UniProtKB-SubCell.
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; IEA:UniProtKB-EC.
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:1901214; P:regulation of neuron death; IBA:GO_Central.
DR GO; GO:0048678; P:response to axon injury; IEA:InterPro.
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; PF00536; SAM_1; 1.
DR Pfam; PF07647; SAM_2; 1.
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; 1.
DR PROSITE; PS50104; TIR; 1.
PE 1: Evidence at protein level;
KW Cell projection; Cytoplasm; Differentiation; Hydrolase; Immunity;
KW Innate immunity; Mitochondrion; NAD; Neurogenesis; Phosphoprotein;
KW Reference proteome; Repeat; Synapse; Transit peptide.
FT TRANSIT 1..?
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN ?..713
FT /note="NAD(+) hydrolase SARM1"
FT /id="PRO_0000448790"
FT REPEAT 53..96
FT /note="ARM 1"
FT /evidence="ECO:0000255"
FT REPEAT 110..149
FT /note="ARM 2"
FT /evidence="ECO:0000255"
FT REPEAT 151..189
FT /note="ARM 3"
FT /evidence="ECO:0000255"
FT REPEAT 192..231
FT /note="ARM 4"
FT /evidence="ECO:0000255"
FT REPEAT 233..276
FT /note="ARM 5"
FT /evidence="ECO:0000255"
FT REPEAT 277..310
FT /note="ARM 6"
FT /evidence="ECO:0000255"
FT REPEAT 311..350
FT /note="ARM 7"
FT /evidence="ECO:0000255"
FT REPEAT 355..398
FT /note="ARM 8"
FT /evidence="ECO:0000255"
FT DOMAIN 408..472
FT /note="SAM 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00184"
FT DOMAIN 478..537
FT /note="SAM 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00184"
FT DOMAIN 552..695
FT /note="TIR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204"
FT ACT_SITE 634
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204"
FT BINDING 99
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 106
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 145..153
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 186..189
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 561..562
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 591
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /ligand_label="2"
FT /ligand_note="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q6SZW1"
FT CONFLICT 107
FT /note="R -> Q (in Ref. 2; AAI63770)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 713 AA; 80332 MW; DA9275DEE56C4559 CRC64;
MFLSLVVYLS KICRYLSMFS SDRLTVPEYV SSRLHNRRTA PDPRAVSPGI STDVQAVLDG
SLPALRSAIR TLRSSKDTGD LEETRRAIAE TFQLVEEAWV LPTVGRRVAE EICNRIRLDG
GLELLLQLMQ TPAVEITYES AKLLEQILVS ENRDYVARMG LGVILNLTRE QEDAQLARSV
SGILEHMFKH TEETSAQLIT NGALDTILYW CRGTDPTVLR HCAVALSNCA MYGGHRCQRL
MIEKQAAEWL FPLAFSKEDE LIRFHACLAV AVLAANREME KEVVKSGTLE LVEPFIASLD
PDEFARNMLD SADSMQGRTA ADLQHLLPLL DGTRLEGKCI AAFYLCVETS IKSRQRNTKI
FQEIGAVQSL KRIVMYSSNA TVCSLAKRAL KMMSEEVPRR ILSSVPNWKS GEVQTWLQQI
GFSAFSERFQ ELQVDGDLLL NITEQDLIQD LGMTSGLTRK RFLRDLRVLK TYANYSTCDP
NNLADWLADA DPRFRQYTYG LVQSGVDRNN IVHITDQQLL TDCHVENGIH RAKILSAARR
PSKPCLTDSQ PKGPDVFISY RRTTGSQLAS LLKVHLQLRG FSVFIDVEKL EAGRFEEKLI
TSVQRARNFI LVLSANALDK CMGDVAMKDW VHKEIVTALN GKKNIVPVTD NFVWPDPTSL
PEDMSTILKF NGIKWSHEYQ EATIEKILRF LEGCPSQEKP DGAKTDKKEP QKK
