SARM1_PIG
ID SARM1_PIG Reviewed; 725 AA.
AC I3L5V6;
DT 06-FEB-2013, integrated into UniProtKB/Swiss-Prot.
DT 11-JUL-2012, sequence version 1.
DT 03-AUG-2022, entry version 50.
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:22366489};
DE Flags: Precursor;
GN Name=SARM1 {ECO:0000303|PubMed:22366489};
OS Sus scrofa (Pig).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Suina; Suidae; Sus.
OX NCBI_TaxID=9823;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RX PubMed=22366489; DOI=10.1016/j.dci.2012.02.001;
RA Zhou X., Jiang T., Du X., Zhou P., Jiang Z., Michal J.J., Liu B.;
RT "Molecular characterization of porcine SARM1 and its role in regulating
RT TLRs signaling during highly pathogenic porcine reproductive and
RT respiratory syndrome virus infection in vivo.";
RL Dev. Comp. Immunol. 39:117-126(2013).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RG Porcine genome sequencing project;
RL Submitted (NOV-2009) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: NAD(+) hydrolase, which plays a key role in axonal
CC degeneration following injury by regulating NAD(+) metabolism (By
CC similarity). Acts as a negative regulator of MYD88- and TRIF-dependent
CC 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
CC (PubMed:22366489). Wallerian degeneration is triggered by NAD(+)
CC depletion: in response to injury, SARM1 is activated and catalyzes
CC cleavage of NAD(+) into ADP-D-ribose (ADPR), cyclic ADPR (cADPR) and
CC nicotinamide; NAD(+) cleavage promoting cytoskeletal degradation and
CC axon destruction (By similarity). Also able to hydrolyze NADP(+), but
CC not other NAD(+)-related molecules (By similarity). Can activate
CC neuronal cell death in response to stress (By similarity). Regulates
CC dendritic arborization through the MAPK4-JNK pathway (By similarity).
CC Involved in innate immune response: inhibits both TICAM1/TRIF- and
CC MYD88-dependent activation of JUN/AP-1, TRIF-dependent activation of
CC NF-kappa-B and IRF3, and the phosphorylation of MAPK14/p38 (By
CC similarity). {ECO:0000250|UniProtKB:Q6PDS3,
CC ECO:0000250|UniProtKB:Q6SZW1, ECO:0000269|PubMed:22366489}.
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 (By similarity). Interacts with MAPK10/JNK3 and SDC2 (via
CC cytoplasmic domain) (By similarity). {ECO:0000250|UniProtKB:Q6PDS3,
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 -!- TISSUE SPECIFICITY: Highest expression seen in the spleen and the
CC brain, followed by lung, kidney, liver and other tissues.
CC {ECO:0000269|PubMed:22366489}.
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-549 by JNK kinases (MAPK8, MAPK9 and /or
CC MAPK10) enhance the NAD(+) hydrolase (NADase) activity. Phosphorylation
CC at Ser-549 and subsequent activation takes place in response to
CC oxidative stress conditions and inhibits mitochondrial respiration.
CC {ECO:0000250|UniProtKB:Q6SZW1}.
CC -!- SIMILARITY: Belongs to the SARM1 family. {ECO:0000305}.
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DR EMBL; FP325197; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR AlphaFoldDB; I3L5V6; -.
DR SMR; I3L5V6; -.
DR STRING; 9823.ENSSSCP00000019407; -.
DR PaxDb; I3L5V6; -.
DR PeptideAtlas; I3L5V6; -.
DR PRIDE; I3L5V6; -.
DR eggNOG; KOG3678; Eukaryota.
DR HOGENOM; CLU_003286_2_0_1; -.
DR InParanoid; I3L5V6; -.
DR TreeFam; TF315263; -.
DR Proteomes; UP000008227; Unplaced.
DR Proteomes; UP000314985; Unplaced.
DR Genevisible; I3L5V6; SS.
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:0030425; C:dendrite; ISS:UniProtKB.
DR GO; GO:0005874; C:microtubule; ISS:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR GO; GO:0045202; C:synapse; ISS:UniProtKB.
DR GO; GO:0050135; F:NAD(P)+ nucleosidase activity; IEA:UniProtKB-EC.
DR GO; GO:0003953; F:NAD+ nucleosidase activity; ISS: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; ISS: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; ISS:UniProtKB.
DR GO; GO:0048814; P:regulation of dendrite morphogenesis; ISS:UniProtKB.
DR GO; GO:1901214; P:regulation of neuron death; ISS:UniProtKB.
DR GO; GO:0048678; P:response to axon injury; ISS:UniProtKB.
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 2: Evidence at transcript 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..725
FT /note="NAD(+) hydrolase SARM1"
FT /id="PRO_0000420904"
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..194
FT /note="ARM 3"
FT /evidence="ECO:0000255"
FT REPEAT 197..236
FT /note="ARM 4"
FT /evidence="ECO:0000255"
FT REPEAT 238..281
FT /note="ARM 5"
FT /evidence="ECO:0000255"
FT REPEAT 282..315
FT /note="ARM 6"
FT /evidence="ECO:0000255"
FT REPEAT 316..355
FT /note="ARM 7"
FT /evidence="ECO:0000255"
FT REPEAT 360..403
FT /note="ARM 8"
FT /evidence="ECO:0000255"
FT DOMAIN 413..477
FT /note="SAM 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00184"
FT DOMAIN 483..549
FT /note="SAM 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00184"
FT DOMAIN 561..704
FT /note="TIR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204"
FT REGION 705..725
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 643
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..158
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 191..194
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 570..571
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 600
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 549
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q6SZW1"
FT MOD_RES 559
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q6PDS3"
SQ SEQUENCE 725 AA; 79792 MW; 07FB8D811BE139B3 CRC64;
MVLTILFSAY KLCRFFAMSS PRPGAERLAV PGPDGGGGAG PWWTAGGRGP REVSPGVGAE
VQGALERALP ELQQALSALK QAGGGRAVGA GLAEVFQLVE EAWLLPAMGR EVAQGLCDAI
RLEGGLDLLL RLLQAPELET RVQAARLLEQ ILVAENRRDR VARIGLGVIL NLAKEREPVE
LARSVAGILE HMFKHSEETC QRLVAAGGLD AVLYWCRRTD PALLRHCALA LANCAMHGGQ
AAQRRMVEKR AAEWLFPLAF SKEDELLRLH ACLAVAVLAT NKEVEREVER SGTLALVEPL
VASLDPGRFA RCLVDASDTS QGRGPDDLQR LVPLLDSSRM EAQCIGAFYL CAEAVIMHIK
NRNKVFSDIG AIQSLKRLVS YSTNGTTSAL AKRALRLLGE EVPRPILPCV ASWKEAEVQT
WLQQIGFSQY CESFREQQVD GDLLLRLTEE ELQTDLGMKS GITRKRFFRE LTELKTFANY
ATCDRSNLAD WLGSLDPRFR QYTYGLVSCG LDRSLLHRVS EQQLLEDCGI RLGVHRVRIL
TAAREMLHSP LPCTGSKPSG DVPDVFISYR RNSGSQLASL LKVHLQLHGF SVFIDVEKLE
AGKFEDKLIQ SIMSARNFVL VLSAGALDKC MQDHDCKDWV HKEIVTALSC GKNIVPVIDG
FEWPEPHTLP EDMQAVLTFN GIKWSHEYQE ATIEKIIRFL QGRSSRDSSA GSDTSLEGAA
PMGPT
