A1IA2_LOXIN
ID A1IA2_LOXIN Reviewed; 285 AA.
AC P0CE84; P83046; Q2XQV2; Q6W8Q4;
DT 23-MAR-2010, integrated into UniProtKB/Swiss-Prot.
DT 23-MAR-2010, sequence version 1.
DT 03-AUG-2022, entry version 35.
DE RecName: Full=Dermonecrotic toxin LiSicTox-alphaIA2aii;
DE EC=4.6.1.- {ECO:0000250|UniProtKB:Q4ZFU2};
DE AltName: Full=Dermonecrotic toxin 2;
DE Short=DT2 {ECO:0000303|PubMed:21590705};
DE Short=LiRecDT2 {ECO:0000303|PubMed:17900646, ECO:0000303|PubMed:21590705};
DE AltName: Full=LiP2;
DE Short=P2 {ECO:0000303|PubMed:9790962};
DE AltName: Full=Phospholipase D;
DE Short=PLD;
DE AltName: Full=Sphingomyelin phosphodiesterase D 2;
DE Short=SMD 2;
DE Short=SMase D 2;
DE Short=Sphingomyelinase D 2;
DE Flags: Precursor; Fragment;
OS Loxosceles intermedia (Brown spider).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; Araneae;
OC Araneomorphae; Haplogynae; Scytodoidea; Sicariidae; Loxosceles.
OX NCBI_TaxID=58218;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], CATALYTIC ACTIVITY, AND FUNCTION.
RC TISSUE=Venom gland;
RX PubMed=16581177; DOI=10.1016/j.biochi.2006.02.008;
RA da Silveira R.B., Pigozzo R.B., Chaim O.M., Appel M.H., Dreyfuss J.L.,
RA Toma L., Mangili O.C., Gremski W., Dietrich C.P., Nader H.B., Veiga S.S.;
RT "Molecular cloning and functional characterization of two isoforms of
RT dermonecrotic toxin from Loxosceles intermedia (Brown spider) venom
RT gland.";
RL Biochimie 88:1241-1253(2006).
RN [2]
RP PROTEIN SEQUENCE OF 27-55, FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR
RP LOCATION.
RC TISSUE=Venom;
RX PubMed=9790962; DOI=10.1006/bbrc.1998.9474;
RA Tambourgi D.V., Magnoli F.C., van den Berg C.W., Morgan B.P.,
RA de Araujo P.S., Alves E.W., Da Silva W.D.;
RT "Sphingomyelinases in the venom of the spider Loxosceles intermedia are
RT responsible for both dermonecrosis and complement-dependent hemolysis.";
RL Biochem. Biophys. Res. Commun. 251:366-373(1998).
RN [3]
RP FUNCTION, AND BIOASSAY.
RX PubMed=17900646; DOI=10.1016/j.toxicon.2007.08.001;
RA Ribeiro R.O., Chaim O.M., da Silveira R.B., Gremski L.H., Sade Y.B.,
RA Paludo K.S., Senff-Ribeiro A., de Moura J., Chavez-Olortegui C.,
RA Gremski W., Nader H.B., Veiga S.S.;
RT "Biological and structural comparison of recombinant phospholipase D toxins
RT from Loxosceles intermedia (brown spider) venom.";
RL Toxicon 50:1162-1174(2007).
RN [4]
RP FUNCTION.
RX PubMed=21590705; DOI=10.1002/jcb.23177;
RA Chaves-Moreira D., Souza F.N., Fogaca R.T., Mangili O.C., Gremski W.,
RA Senff-Ribeiro A., Chaim O.M., Veiga S.S.;
RT "The relationship between calcium and the metabolism of plasma membrane
RT phospholipids in hemolysis induced by brown spider venom phospholipase-D
RT toxin.";
RL J. Cell. Biochem. 112:2529-2540(2011).
CC -!- FUNCTION: Dermonecrotic toxins cleave the phosphodiester linkage
CC between the phosphate and headgroup of certain phospholipids
CC (sphingolipid and lysolipid substrates), forming an alcohol (often
CC choline) and a cyclic phosphate (By similarity). This toxin acts on
CC sphingomyelin (SM) with high activity (PubMed:16581177,
CC PubMed:9790962). It may also act on ceramide phosphoethanolamine (CPE),
CC lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE),
CC but not on lysophosphatidylserine (LPS), and lysophosphatidylglycerol
CC (LPG) (By similarity). It acts by transphosphatidylation, releasing
CC exclusively cyclic phosphate products as second products (By
CC similarity). Shows high hemolytic activity. Induces dermonecrosis,
CC vascular permeability, edema, inflammatory response, and platelet
CC aggregation (PubMed:16581177, PubMed:17900646). Also shows cytotoxicity
CC against renal epithelial cells (PubMed:17900646). In addition, also
CC induces hemolysis in a complement-dependent manner and probably also in
CC a complement-independent manner (PubMed:9790962, PubMed:17900646). The
CC hemolysis provoked in a complement-independent manner may be composed
CC of several steps (By similarity). The toxin may bind to erythrocyte
CC membranes, may hydrolyze membrane phospholipids (SM and LPC) thus
CC generating metabolism products that may cause hemolysis, probably by
CC provoking an increase of calcium inside cells (By similarity). The
CC calcium influx may be due to the opening of L-type calcium channels,
CC since L-type calcium channel blockers inhibit calcium influx (By
CC similarity). In vivo, is lethal to mice when intraperitoneally injected
CC (PubMed:17900646). {ECO:0000250|UniProtKB:A0A0D4WTV1,
CC ECO:0000250|UniProtKB:P0CE80, ECO:0000269|PubMed:16581177,
CC ECO:0000269|PubMed:17900646, ECO:0000269|PubMed:21590705,
CC ECO:0000269|PubMed:9790962}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an N-(acyl)-sphingosylphosphocholine = an N-(acyl)-sphingosyl-
CC 1,3-cyclic phosphate + choline; Xref=Rhea:RHEA:60652,
CC ChEBI:CHEBI:15354, ChEBI:CHEBI:64583, ChEBI:CHEBI:143892;
CC Evidence={ECO:0000305|PubMed:16581177, ECO:0000305|PubMed:9790962};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an N-(acyl)-sphingosylphosphoethanolamine = an N-(acyl)-
CC sphingosyl-1,3-cyclic phosphate + ethanolamine; Xref=Rhea:RHEA:60648,
CC ChEBI:CHEBI:57603, ChEBI:CHEBI:143891, ChEBI:CHEBI:143892;
CC Evidence={ECO:0000250|UniProtKB:A0A0D4WTV1};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1-acyl-sn-glycero-3-phosphocholine = a 1-acyl-sn-glycero-
CC 2,3-cyclic phosphate + choline; Xref=Rhea:RHEA:60700,
CC ChEBI:CHEBI:15354, ChEBI:CHEBI:58168, ChEBI:CHEBI:143947;
CC Evidence={ECO:0000250|UniProtKB:A0A0D4WTV1};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1-acyl-sn-glycero-3-phosphoethanolamine = a 1-acyl-sn-
CC glycero-2,3-cyclic phosphate + ethanolamine; Xref=Rhea:RHEA:60704,
CC ChEBI:CHEBI:57603, ChEBI:CHEBI:64381, ChEBI:CHEBI:143947;
CC Evidence={ECO:0000250|UniProtKB:A0A0D4WTV1};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:Q8I914};
CC Note=Binds 1 Mg(2+) ion per subunit. {ECO:0000250|UniProtKB:Q8I914};
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:9790962}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:9790962}.
CC -!- SIMILARITY: Belongs to the arthropod phospholipase D family. Class II
CC subfamily. Class IIa sub-subfamily. {ECO:0000305}.
CC -!- CAUTION: The most common activity assay for dermonecrotic toxins
CC detects enzymatic activity by monitoring choline release from
CC substrate. Liberation of choline from sphingomyelin (SM) or
CC lysophosphatidylcholine (LPC) is commonly assumed to result from
CC substrate hydrolysis, giving either ceramide-1-phosphate (C1P) or
CC lysophosphatidic acid (LPA), respectively, as a second product.
CC However, two studies from Lajoie and colleagues (2013 and 2015) report
CC the observation of exclusive formation of cyclic phosphate products as
CC second products, resulting from intramolecular transphosphatidylation.
CC Cyclic phosphates have vastly different biological properties from
CC their monoester counterparts, and they may be relevant to the pathology
CC of brown spider envenomation. {ECO:0000250|UniProtKB:A0A0D4WTV1,
CC ECO:0000250|UniProtKB:A0A0D4WV12, ECO:0000250|UniProtKB:Q4ZFU2}.
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DR EMBL; DQ266399; ABB69098.1; -; mRNA.
DR AlphaFoldDB; P0CE84; -.
DR SMR; P0CE84; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0016829; F:lyase activity; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0008081; F:phosphoric diester hydrolase activity; IEA:InterPro.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR GO; GO:0044179; P:hemolysis in another organism; IEA:UniProtKB-KW.
DR GO; GO:0016042; P:lipid catabolic process; IEA:UniProtKB-KW.
DR Gene3D; 3.20.20.190; -; 1.
DR InterPro; IPR017946; PLC-like_Pdiesterase_TIM-brl.
DR SUPFAM; SSF51695; SSF51695; 1.
PE 1: Evidence at protein level;
KW Cytolysis; Dermonecrotic toxin; Direct protein sequencing; Disulfide bond;
KW Glycoprotein; Hemolysis; Lipid degradation; Lipid metabolism; Lyase;
KW Magnesium; Metal-binding; Secreted; Toxin; Zymogen.
FT PROPEP <1..5
FT /id="PRO_0000392749"
FT CHAIN 6..285
FT /note="Dermonecrotic toxin LiSicTox-alphaIA2aii"
FT /id="PRO_0000392750"
FT ACT_SITE 17
FT /evidence="ECO:0000250|UniProtKB:Q8I914"
FT ACT_SITE 53
FT /note="Nucleophile"
FT /evidence="ECO:0000250|UniProtKB:Q8I914"
FT BINDING 37
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:Q8I914"
FT BINDING 39
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:Q8I914"
FT BINDING 97
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:Q8I914"
FT CARBOHYD 262
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 57..63
FT /evidence="ECO:0000250|UniProtKB:P0CE80"
FT DISULFID 59..202
FT /evidence="ECO:0000250|UniProtKB:P0CE80"
FT NON_TER 1
SQ SEQUENCE 285 AA; 31920 MW; EAF527531A317F53 CRC64;
DVEERADKRR PIWIMGHMVN AIAQIDEFVN LGANSIETDV SFDDNANPEY TYHGIPCDCG
RSCLKWENFN DFLKGLRSAT TPGNAKYQAK LILVVFDLKT GSLYDNQANE AGKKLAKNLL
KHYWNNGNNG GRAYIVLSIP DLNHYPLIKG FKDQLTQDGH PELMDKVGHD FSGNDAIGDV
GNAYKKAGIS GHVWQSDGIT NCLLRGLDRV KQAIANRDSA NGFINKVYYW TVDKRATTRD
ALDAGVDGVM TNYPDVITDV LNESAYKNKF RVASYEDNPW ETFKK
