SARM1_RAT
ID SARM1_RAT Reviewed; 724 AA.
AC D3ZUM2;
DT 10-FEB-2021, integrated into UniProtKB/Swiss-Prot.
DT 20-APR-2010, sequence version 1.
DT 03-AUG-2022, entry version 87.
DE RecName: Full=NAD(+) hydrolase SARM1 {ECO:0000305};
DE Short=NADase SARM1 {ECO:0000305};
DE EC=3.2.2.6 {ECO:0000250|UniProtKB:Q6SZW1};
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|PubMed:32968873};
DE Flags: Precursor;
GN Name=Sarm1 {ECO:0000303|PubMed:32968873, ECO:0000312|RGD:1310078};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway;
RX PubMed=15057822; DOI=10.1038/nature02426;
RA Gibbs R.A., Weinstock G.M., Metzker M.L., Muzny D.M., Sodergren E.J.,
RA Scherer S., Scott G., Steffen D., Worley K.C., Burch P.E., Okwuonu G.,
RA Hines S., Lewis L., Deramo C., Delgado O., Dugan-Rocha S., Miner G.,
RA Morgan M., Hawes A., Gill R., Holt R.A., Adams M.D., Amanatides P.G.,
RA Baden-Tillson H., Barnstead M., Chin S., Evans C.A., Ferriera S.,
RA Fosler C., Glodek A., Gu Z., Jennings D., Kraft C.L., Nguyen T.,
RA Pfannkoch C.M., Sitter C., Sutton G.G., Venter J.C., Woodage T., Smith D.,
RA Lee H.-M., Gustafson E., Cahill P., Kana A., Doucette-Stamm L.,
RA Weinstock K., Fechtel K., Weiss R.B., Dunn D.M., Green E.D.,
RA Blakesley R.W., Bouffard G.G., De Jong P.J., Osoegawa K., Zhu B., Marra M.,
RA Schein J., Bosdet I., Fjell C., Jones S., Krzywinski M., Mathewson C.,
RA Siddiqui A., Wye N., McPherson J., Zhao S., Fraser C.M., Shetty J.,
RA Shatsman S., Geer K., Chen Y., Abramzon S., Nierman W.C., Havlak P.H.,
RA Chen R., Durbin K.J., Egan A., Ren Y., Song X.-Z., Li B., Liu Y., Qin X.,
RA Cawley S., Cooney A.J., D'Souza L.M., Martin K., Wu J.Q.,
RA Gonzalez-Garay M.L., Jackson A.R., Kalafus K.J., McLeod M.P.,
RA Milosavljevic A., Virk D., Volkov A., Wheeler D.A., Zhang Z., Bailey J.A.,
RA Eichler E.E., Tuzun E., Birney E., Mongin E., Ureta-Vidal A., Woodwark C.,
RA Zdobnov E., Bork P., Suyama M., Torrents D., Alexandersson M., Trask B.J.,
RA Young J.M., Huang H., Wang H., Xing H., Daniels S., Gietzen D., Schmidt J.,
RA Stevens K., Vitt U., Wingrove J., Camara F., Mar Alba M., Abril J.F.,
RA Guigo R., Smit A., Dubchak I., Rubin E.M., Couronne O., Poliakov A.,
RA Huebner N., Ganten D., Goesele C., Hummel O., Kreitler T., Lee Y.-A.,
RA Monti J., Schulz H., Zimdahl H., Himmelbauer H., Lehrach H., Jacob H.J.,
RA Bromberg S., Gullings-Handley J., Jensen-Seaman M.I., Kwitek A.E.,
RA Lazar J., Pasko D., Tonellato P.J., Twigger S., Ponting C.P., Duarte J.M.,
RA Rice S., Goodstadt L., Beatson S.A., Emes R.D., Winter E.E., Webber C.,
RA Brandt P., Nyakatura G., Adetobi M., Chiaromonte F., Elnitski L.,
RA Eswara P., Hardison R.C., Hou M., Kolbe D., Makova K., Miller W.,
RA Nekrutenko A., Riemer C., Schwartz S., Taylor J., Yang S., Zhang Y.,
RA Lindpaintner K., Andrews T.D., Caccamo M., Clamp M., Clarke L., Curwen V.,
RA Durbin R.M., Eyras E., Searle S.M., Cooper G.M., Batzoglou S., Brudno M.,
RA Sidow A., Stone E.A., Payseur B.A., Bourque G., Lopez-Otin C., Puente X.S.,
RA Chakrabarti K., Chatterji S., Dewey C., Pachter L., Bray N., Yap V.B.,
RA Caspi A., Tesler G., Pevzner P.A., Haussler D., Roskin K.M., Baertsch R.,
RA Clawson H., Furey T.S., Hinrichs A.S., Karolchik D., Kent W.J.,
RA Rosenbloom K.R., Trumbower H., Weirauch M., Cooper D.N., Stenson P.D.,
RA Ma B., Brent M., Arumugam M., Shteynberg D., Copley R.R., Taylor M.S.,
RA Riethman H., Mudunuri U., Peterson J., Guyer M., Felsenfeld A., Old S.,
RA Mockrin S., Collins F.S.;
RT "Genome sequence of the Brown Norway rat yields insights into mammalian
RT evolution.";
RL Nature 428:493-521(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP PHOSPHORYLATION AT SER-548, AND MUTAGENESIS OF SER-548.
RX PubMed=32968873; DOI=10.1007/s12035-020-02132-9;
RA Xue T., Sun Q., Zhang Y., Wu X., Shen H., Li X., Wu J., Li H., Wang Z.,
RA Chen G.;
RT "Phosphorylation at S548 as a functional switch of Sterile Alpha and TIR
RT Motif-containing 1 in cerebral ischemia/reperfusion injury in rats.";
RL Mol. Neurobiol. 58:453-469(2021).
CC -!- FUNCTION: NAD(+) hydrolase, which plays a key role in axonal
CC degeneration following injury by regulating NAD(+) metabolism. Acts as
CC a negative regulator of MYD88- and TRIF-dependent toll-like receptor
CC signaling pathway by promoting Wallerian degeneration, an injury-
CC induced form of programmed subcellular death which involves
CC degeneration of an axon distal to the injury site. Wallerian
CC degeneration is triggered by NAD(+) depletion: in response to injury,
CC SARM1 is activated and catalyzes cleavage of NAD(+) into ADP-D-ribose
CC (ADPR), cyclic ADPR (cADPR) and nicotinamide; NAD(+) cleavage promoting
CC cytoskeletal degradation and axon destruction. Also able to hydrolyze
CC NADP(+), but not other NAD(+)-related molecules. Can activate neuronal
CC cell death in response to stress. Regulates dendritic arborization
CC through the MAPK4-JNK pathway. 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. {ECO:0000250|UniProtKB:Q6PDS3,
CC ECO:0000250|UniProtKB:Q6SZW1}.
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:0000250|UniProtKB:Q6SZW1};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16302;
CC Evidence={ECO:0000250|UniProtKB:Q6SZW1};
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 Interacts with TICAM1/TRIF and thereby interferes with TICAM1/TRIF
CC function. Interacts with MAPK10/JNK3 and SDC2 (via cytoplasmic domain).
CC {ECO:0000250|UniProtKB:Q6PDS3, 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 -!- PTM: Phosphorylation at Ser-548 by JNK kinases (MAPK8, MAPK9 and /or
CC MAPK10) enhance the NAD(+) hydrolase (NADase) activity
CC (PubMed:32968873). Phosphorylation at Ser-548 and subsequent activation
CC takes place in response to oxidative stress conditions and inhibits
CC mitochondrial respiration (By similarity). Phosphorylation at Ser-548
CC increases in response to cerebral ischemia/reperfusion (I/R) injury
CC (PubMed:32968873). {ECO:0000250|UniProtKB:Q6SZW1,
CC ECO:0000269|PubMed:32968873}.
CC -!- SIMILARITY: Belongs to the SARM1 family. {ECO:0000305}.
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DR EMBL; AABR07030074; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH473948; EDM05357.1; -; Genomic_DNA.
DR RefSeq; NP_001099287.1; NM_001105817.1.
DR AlphaFoldDB; D3ZUM2; -.
DR SMR; D3ZUM2; -.
DR STRING; 10116.ENSRNOP00000013639; -.
DR jPOST; D3ZUM2; -.
DR PaxDb; D3ZUM2; -.
DR PeptideAtlas; D3ZUM2; -.
DR PRIDE; D3ZUM2; -.
DR Ensembl; ENSRNOT00000013639; ENSRNOP00000013639; ENSRNOG00000010244.
DR GeneID; 287545; -.
DR KEGG; rno:287545; -.
DR CTD; 23098; -.
DR RGD; 1310078; Sarm1.
DR eggNOG; KOG3678; Eukaryota.
DR GeneTree; ENSGT00390000004155; -.
DR HOGENOM; CLU_003286_2_0_1; -.
DR InParanoid; D3ZUM2; -.
DR OMA; CVPSWKE; -.
DR OrthoDB; 206466at2759; -.
DR PhylomeDB; D3ZUM2; -.
DR TreeFam; TF315263; -.
DR PRO; PR:D3ZUM2; -.
DR Proteomes; UP000002494; Chromosome 10.
DR Proteomes; UP000234681; Chromosome 10.
DR Bgee; ENSRNOG00000010244; Expressed in frontal cortex and 11 other tissues.
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; ISO:RGD.
DR GO; GO:0030425; C:dendrite; ISO:RGD.
DR GO; GO:0031315; C:extrinsic component of mitochondrial outer membrane; ISO:RGD.
DR GO; GO:0005874; C:microtubule; ISO:RGD.
DR GO; GO:0015630; C:microtubule cytoskeleton; ISO:RGD.
DR GO; GO:0005739; C:mitochondrion; ISO:RGD.
DR GO; GO:0045202; C:synapse; ISO:RGD.
DR GO; GO:0050135; F:NAD(P)+ nucleosidase activity; IEA:UniProtKB-EC.
DR GO; GO:0003953; F:NAD+ nucleosidase activity; ISO:RGD.
DR GO; GO:0061809; F:NAD+ nucleotidase, cyclic ADP-ribose generating; ISO:RGD.
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; ISO:RGD.
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; ISO:RGD.
DR GO; GO:0042981; P:regulation of apoptotic process; ISO:RGD.
DR GO; GO:0048814; P:regulation of dendrite morphogenesis; ISO:RGD.
DR GO; GO:0043523; P:regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:1901214; P:regulation of neuron death; ISO:RGD.
DR GO; GO:0048678; P:response to axon injury; ISO:RGD.
DR GO; GO:0009749; P:response to glucose; ISO:RGD.
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 Cell projection; Cytoplasm; Differentiation; Hydrolase; Immunity;
KW Innate immunity; Mitochondrion; NAD; Neurogenesis; Phosphoprotein;
KW 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_0000452004"
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 703..724
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 703..718
FT /note="Polar residues"
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:0000255|PROSITE-ProRule:PRU00204"
FT BINDING 599
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /ligand_label="2"
FT /ligand_note="substrate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204"
FT MOD_RES 548
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:32968873"
FT MOD_RES 558
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q6PDS3"
FT MUTAGEN 548
FT /note="S->A: Reduced infarct size, neuronal death and
FT neurobehavioral dysfunction in response to cerebral
FT ischemia/reperfusion (I/R) injury."
FT /evidence="ECO:0000269|PubMed:32968873"
SQ SEQUENCE 724 AA; 79688 MW; 69C5AC996CB2A2D3 CRC64;
MVLTLLFSAY KLCRFFIMSG PRPGADRLTV PGPDRSGGTS PWWAAGGRGS REVSPGVGTE
VQGALERSLP ELQQALSELK QASAAQAVGA GLAEVFQLVE EAWLLPAVGR EVAQGLCDAI
RLDGGLDLLL RLLQAPELET RVQAARLLEQ ILVAENRDRV ARIGLGVILN LSKEREPVEL
ARSVAGILEH MFKHSEETCQ RLVAAGGLDA VLYWCRRTDP ALLRHCALAL ANCALHGGQT
VQRCMVEKRA AEWLFPLAFS KEDELLRLHA CLAVAVLATN KEVEREVEHS GTLALVEPLV
ASLDPGRFAR CLVDASDTSQ GRGPDDLQSL VLLLDSSRLE AQCIGAFYLC AEAAIKSLQG
KTKVFSDIGA IQSLKRLVSY STNGTTSTLA KRALRLLGEE VPRRILPCVA SWKEAEVQTW
LQQIGFSQYC ENFRDQQVDG DLLLRLTDEE LQTDLGMKSS ITRKRFFREL TELKTFASYA
TCDRSNLADW LGSLDPRFRQ YTYGLVSCGL DRSLLHRVSE QQLLEDCGIR LGVHRTRILS
AAREMLHSPL PCTGGKPSGD TPDVFISYRR NSGSQLASLL KVHLQLHGFS VFIDVEKLEA
GKFEDKLIQS VMAARNFVLV LSAGALDKCM QDHECKDWVH KEIVTALSCS KNIVPIIDGF
EWPEPQALPE DMQAVLTFNG IKWSHEYQEA TIEKIIRFLQ GRPSQDSSAG SDTSLEGATS
MGLP
