PA2BC_VIPAA
ID PA2BC_VIPAA Reviewed; 138 AA.
AC P11407;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1989, sequence version 1.
DT 03-AUG-2022, entry version 128.
DE RecName: Full=Basic phospholipase A2 ammodytoxin C;
DE Short=AtxC;
DE Short=svPLA2;
DE EC=3.1.1.4;
DE AltName: Full=Phosphatidylcholine 2-acylhydrolase;
DE Flags: Precursor;
OS Vipera ammodytes ammodytes (Western sand viper).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Lepidosauria; Squamata; Bifurcata; Unidentata; Episquamata; Toxicofera;
OC Serpentes; Colubroidea; Viperidae; Viperinae; Vipera.
OX NCBI_TaxID=8705;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Northern Balkan; TISSUE=Venom gland;
RX PubMed=2740219; DOI=10.1093/nar/17.11.4367;
RA Pungercar J., Kordis D., Jerala R., Trstenjak-Prebanda M., Dolinar M.,
RA Curin-Serbec V., Komel R., Gubensek F.;
RT "Amino acid sequence of ammodytoxin C as deduced from cDNA.";
RL Nucleic Acids Res. 17:4367-4367(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Venom gland;
RX PubMed=8797839; DOI=10.1111/j.1432-1033.1996.0083h.x;
RA Kordis D., Gubensek F.;
RT "Ammodytoxin C gene helps to elucidate the irregular structure of
RT Crotalinae group II phospholipase A2 genes.";
RL Eur. J. Biochem. 240:83-90(1996).
RN [3]
RP PROTEIN SEQUENCE OF 17-138.
RC STRAIN=Northern Balkan; TISSUE=Venom;
RX PubMed=2597708; DOI=10.1016/0167-4838(89)90218-5;
RA Krizaj I., Turk D., Ritonja A., Gubensek F.;
RT "Primary structure of ammodytoxin C further reveals the toxic site of
RT ammodytoxin.";
RL Biochim. Biophys. Acta 999:198-202(1989).
RN [4]
RP REVIEW.
RX PubMed=21726572; DOI=10.1016/j.toxicon.2011.06.009;
RA Krizaj I.;
RT "Ammodytoxin: a window into understanding presynaptic toxicity of secreted
RT phospholipases A(2) and more.";
RL Toxicon 58:219-229(2011).
RN [5]
RP BINDING TO AN INTRACELLULAR MEMBRANE PROTEIN (R25).
RX PubMed=9790932; DOI=10.1006/bbrc.1998.9427;
RA Vucemilo N., Copic A., Gubensek F., Krizaj I.;
RT "Identification of a new high-affinity binding protein for neurotoxic
RT phospholipases A2.";
RL Biochem. Biophys. Res. Commun. 251:209-212(1998).
RN [6]
RP TOXIC DOSE.
RX PubMed=10377255; DOI=10.1042/bj3410139;
RA Pungercar J., Krizaj I., Liang N.-S., Gubensek F.;
RT "An aromatic, but not a basic, residue is involved in the toxicity of
RT group-II phospholipase A2 neurotoxins.";
RL Biochem. J. 341:139-145(1999).
RN [7]
RP BINDING TO CALMODULIN.
RX PubMed=11278260; DOI=10.1074/jbc.c100048200;
RA Sribar J., Copic A., Paris A., Sherman N.E., Gubensek F., Fox J.W.,
RA Krizaj I.;
RT "A high affinity acceptor for phospholipase A2 with neurotoxic activity is
RT a calmodulin.";
RL J. Biol. Chem. 276:12493-12496(2001).
RN [8]
RP FUNCTION.
RX PubMed=11600150; DOI=10.1016/s0041-0101(01)00170-2;
RA Fathi B., Rowan E.G., Harvey A.L.;
RT "The facilitatory actions of snake venom phospholipase A(2) neurotoxins at
RT the neuromuscular junction are not mediated through voltage-gated K(+)
RT channels.";
RL Toxicon 39:1871-1882(2001).
RN [9]
RP BINDING TO 14-3-3 PROTEINS GAMMA (YWHAG) AND EPSILON (YWHAE).
RX PubMed=12646224; DOI=10.1016/s0006-291x(03)00228-6;
RA Sribar J., Sherman N.E., Prijatelj P., Faure G., Gubensek F., Fox J.W.,
RA Aitken A., Pungercar J., Krizaj I.;
RT "The neurotoxic phospholipase A2 associates, through a non-phosphorylated
RT binding motif, with 14-3-3 protein gamma and epsilon isoforms.";
RL Biochem. Biophys. Res. Commun. 302:691-696(2003).
RN [10]
RP BINDING TO AN INTRACELLULAR MEMBRANE PROTEIN (R25).
RX PubMed=14572642; DOI=10.1016/s0014-5793(03)01035-4;
RA Sribar J., Copic A., Poljsak-Prijatelj M., Kuret J., Logonder U.,
RA Gubensek F., Krizaj I.;
RT "R25 is an intracellular membrane receptor for a snake venom secretory
RT phospholipase A(2).";
RL FEBS Lett. 553:309-314(2003).
RN [11]
RP FUNCTION.
RC TISSUE=Venom;
RX PubMed=16156665; DOI=10.1021/bi051024r;
RA Petan T., Krizaj I., Gelb M.H., Pungercar J.;
RT "Ammodytoxins, potent presynaptic neurotoxins, are also highly efficient
RT phospholipase A2 enzymes.";
RL Biochemistry 44:12535-12545(2005).
RN [12]
RP FUNCTION, AND BINDING TO COAGULATION FACTOR X (F10).
RX PubMed=16039772; DOI=10.1016/j.biochi.2005.06.015;
RA Prijatelj P., Charnay M., Ivanovski G., Jenko Z., Pungercar J., Krizaj I.,
RA Faure G.;
RT "The C-terminal and beta-wing regions of ammodytoxin A, a neurotoxic
RT phospholipase A2 from Vipera ammodytes ammodytes, are critical for binding
RT to factor Xa and for anticoagulant effect.";
RL Biochimie 88:69-76(2006).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (1.35 ANGSTROMS) OF 17-138, AND DISULFIDE BONDS.
RX PubMed=19857576; DOI=10.1016/j.jsb.2009.10.010;
RA Saul F.A., Prijatelj-Znidarsic P., Vulliez-le Normand B., Villette B.,
RA Raynal B., Pungercar J., Krizaj I., Faure G.;
RT "Comparative structural studies of two natural isoforms of ammodytoxin,
RT phospholipases A2 from Vipera ammodytes ammodytes which differ in
RT neurotoxicity and anticoagulant activity.";
RL J. Struct. Biol. 169:360-369(2010).
CC -!- FUNCTION: Snake venom phospholipase A2 (PLA2) that acts as a
CC presynaptic neurotoxin, an inhibitor of blood coagulation, and has been
CC found to bind with high affinity to intracellular proteins. The
CC response of indirectly stimulated neuromuscular preparations to
CC ammodytoxin (Atx) is triphasic. The first phase, the transient
CC inhibition of the acetylcholine (ACh) release, starts soon after the
CC addition of Atx and lasts for several minutes. This phase is probably
CC independent of Atx enzymatic activity. The effect may be due to the
CC specific binding of the toxin to presynaptic receptors. These
CC receptors, called N-type receptors, are still unidentified. It is
CC noteworthy that a neuronal isoform of the M-type PLA2 receptor (R180)
CC has been identified as a high-affinity receptor for Atx in neuronal
CC plasma membranes. It was demonstrated however that this receptor is not
CC essential for expression of neurotoxicity by Atx. The second phase
CC corresponds to an augmentation of neurotransmitter release. A peak is
CC reached 10-20 min after exposure of the preparation to Atx and is
CC followed by a gradual reduction. In this phase, the enzymatic activity
CC of Atx of the mammalian is not significant. It is speculated that the
CC increased release of neurotransmitter in this phase is induced by the
CC interference of Atx with voltage-gated potassium channels. Measurements
CC of ionic showed however that voltage-gated potassium channels are not
CC affected by Atx. The third phase of the response of neuromuscular
CC preparations to Atx, which corresponds to a complete and irreversible
CC paralysis, is clearly dependent on the hydrolytic activity of the
CC toxin. In addition to its presynaptic neurotoxicity, Atx shows an
CC anticoagulant activity by binding with high affinity to activated
CC coagulation factor X (F10) thus inhibiting the formation of the
CC prothrombinase complex (FX/FV) and its activity (IC(50) is 240 nM).
CC Surprisingly, Atx was discovered to bind intracellular proteins such as
CC calmodulin (CaM), 14-3-3 proteins gamma (YWHAG) and epsilon (YWHAE), as
CC well as R25, a mitochondrial integral membrane protein found in
CC cerebral cortex. These findings raised a doubt about the dogma of the
CC exclusively extracellular action of PLA2s, defended by the potential
CC instability of these molecules in the reducing environment of the
CC eukaryotic cytosol coupled with their possible inability to act as
CC enzymes in this cellular compartment, due to too low concentration of
CC calcium ions. This hypothesis was challenged efficiently by
CC demonstrating the internalization of AtxA into a culture cells, but
CC still remains to be directly demonstrated in vivo (By similarity). PLA2
CC catalyzes the calcium-dependent hydrolysis of the 2-acyl groups in 3-
CC sn-phosphoglycerides. {ECO:0000250, ECO:0000269|PubMed:11600150,
CC ECO:0000269|PubMed:16039772, ECO:0000269|PubMed:16156665}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-diacyl-sn-glycero-3-phosphocholine + H2O = a 1-acyl-sn-
CC glycero-3-phosphocholine + a fatty acid + H(+); Xref=Rhea:RHEA:15801,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:28868,
CC ChEBI:CHEBI:57643, ChEBI:CHEBI:58168; EC=3.1.1.4;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10035, ECO:0000255|PROSITE-
CC ProRule:PRU10036};
CC -!- COFACTOR:
CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108; Evidence={ECO:0000250};
CC Note=Binds 1 Ca(2+) ion. {ECO:0000250};
CC -!- SUBUNIT: Monomer. Binds to calmodulin, coagulation factor X (F10), 14-
CC 3-3 proteins gamma (YWHAG) and epsilon (YWHAE), and R25, a
CC mitochondrial membrane protein. May bind to M-type PLA2 receptor (R-
CC 180).
CC -!- SUBCELLULAR LOCATION: Secreted. Host cytoplasm, host cytosol
CC {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC -!- TOXIC DOSE: LD(50) is 0.36 mg/kg by intravenous injection into mice.
CC {ECO:0000269|PubMed:10377255}.
CC -!- MISCELLANEOUS: Does not affect mKv1.1/KCNA1, rKv1.2/KCNA2,
CC mKv1.3/KCNA3, hKv1.5/KCNA5 and mKv3.1/KCNC1 voltage-gated potassium
CC channels. {ECO:0000305|PubMed:11600150}.
CC -!- SIMILARITY: Belongs to the phospholipase A2 family. Group II subfamily.
CC D49 sub-subfamily. {ECO:0000305}.
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DR EMBL; X15138; CAA33238.1; -; mRNA.
DR EMBL; X76731; CAA54147.1; -; Genomic_DNA.
DR PIR; I51386; I51386.
DR PIR; S04587; PSVIAC.
DR PDB; 3G8H; X-ray; 1.35 A; A=17-138.
DR PDBsum; 3G8H; -.
DR AlphaFoldDB; P11407; -.
DR SMR; P11407; -.
DR EvolutionaryTrace; P11407; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0004623; F:phospholipase A2 activity; IEA:UniProtKB-EC.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR GO; GO:0050482; P:arachidonic acid secretion; IEA:InterPro.
DR GO; GO:0016042; P:lipid catabolic process; IEA:UniProtKB-KW.
DR GO; GO:0006644; P:phospholipid metabolic process; IEA:InterPro.
DR CDD; cd00125; PLA2c; 1.
DR Gene3D; 1.20.90.10; -; 1.
DR InterPro; IPR001211; PLipase_A2.
DR InterPro; IPR033112; PLipase_A2_Asp_AS.
DR InterPro; IPR016090; PLipase_A2_dom.
DR InterPro; IPR036444; PLipase_A2_dom_sf.
DR InterPro; IPR033113; PLipase_A2_His_AS.
DR PANTHER; PTHR11716; PTHR11716; 1.
DR Pfam; PF00068; Phospholip_A2_1; 1.
DR PRINTS; PR00389; PHPHLIPASEA2.
DR SMART; SM00085; PA2c; 1.
DR SUPFAM; SSF48619; SSF48619; 1.
DR PROSITE; PS00119; PA2_ASP; 1.
DR PROSITE; PS00118; PA2_HIS; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Blood coagulation cascade inhibiting toxin; Calcium;
KW Direct protein sequencing; Disulfide bond; Hemostasis impairing toxin;
KW Host cytoplasm; Hydrolase; Lipid degradation; Lipid metabolism;
KW Metal-binding; Neurotoxin; Presynaptic neurotoxin; Secreted; Signal; Toxin.
FT SIGNAL 1..16
FT /evidence="ECO:0000269|PubMed:2597708"
FT CHAIN 17..138
FT /note="Basic phospholipase A2 ammodytoxin C"
FT /evidence="ECO:0000269|PubMed:2597708"
FT /id="PRO_0000022972"
FT ACT_SITE 63
FT /evidence="ECO:0000250|UniProtKB:P14418"
FT ACT_SITE 105
FT /evidence="ECO:0000250|UniProtKB:P14418"
FT BINDING 43
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P59071"
FT BINDING 45
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P59071"
FT BINDING 47
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P59071"
FT BINDING 64
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P59071"
FT SITE 18
FT /note="Putative membrane binding site"
FT SITE 19
FT /note="Putative membrane binding site"
FT SITE 34
FT /note="Putative membrane binding site"
FT SITE 35
FT /note="Putative membrane binding site"
FT SITE 39
FT /note="Putative membrane binding site"
FT SITE 46
FT /note="Putative membrane binding site"
FT SITE 76
FT /note="Putative membrane binding site"
FT SITE 77
FT /note="Putative membrane binding site"
FT SITE 79
FT /note="Putative membrane binding site"
FT SITE 82
FT /note="Putative membrane binding site"
FT SITE 124
FT /note="Putative membrane binding site"
FT SITE 125
FT /note="Putative membrane binding site"
FT SITE 129
FT /note="Putative membrane binding site"
FT DISULFID 42..131
FT /evidence="ECO:0000269|PubMed:19857576,
FT ECO:0007744|PDB:3G8H"
FT DISULFID 44..60
FT /evidence="ECO:0000269|PubMed:19857576,
FT ECO:0007744|PDB:3G8H"
FT DISULFID 59..111
FT /evidence="ECO:0000269|PubMed:19857576,
FT ECO:0007744|PDB:3G8H"
FT DISULFID 65..138
FT /evidence="ECO:0000269|PubMed:19857576,
FT ECO:0007744|PDB:3G8H"
FT DISULFID 66..104
FT /evidence="ECO:0000269|PubMed:19857576,
FT ECO:0007744|PDB:3G8H"
FT DISULFID 73..97
FT /evidence="ECO:0000269|PubMed:19857576,
FT ECO:0007744|PDB:3G8H"
FT DISULFID 91..102
FT /evidence="ECO:0000269|PubMed:19857576,
FT ECO:0007744|PDB:3G8H"
FT HELIX 18..29
FT /evidence="ECO:0007829|PDB:3G8H"
FT HELIX 33..36
FT /evidence="ECO:0007829|PDB:3G8H"
FT STRAND 37..40
FT /evidence="ECO:0007829|PDB:3G8H"
FT TURN 41..43
FT /evidence="ECO:0007829|PDB:3G8H"
FT STRAND 44..47
FT /evidence="ECO:0007829|PDB:3G8H"
FT HELIX 55..68
FT /evidence="ECO:0007829|PDB:3G8H"
FT TURN 75..77
FT /evidence="ECO:0007829|PDB:3G8H"
FT STRAND 82..85
FT /evidence="ECO:0007829|PDB:3G8H"
FT STRAND 88..91
FT /evidence="ECO:0007829|PDB:3G8H"
FT HELIX 96..114
FT /evidence="ECO:0007829|PDB:3G8H"
FT HELIX 116..118
FT /evidence="ECO:0007829|PDB:3G8H"
FT HELIX 121..123
FT /evidence="ECO:0007829|PDB:3G8H"
FT HELIX 128..130
FT /evidence="ECO:0007829|PDB:3G8H"
SQ SEQUENCE 138 AA; 15498 MW; D9F6070A04EB3BB2 CRC64;
MRTLWIVAVC LIGVEGSLLE FGMMILGETG KNPLTSYSFY GCYCGVGGKG TPKDATDRCC
FVHDCCYGNL PDCSPKTDRY KYHRENGAIV CGKGTSCENR ICECDRAAAI CFRKNLKTYN
YIYRNYPDIL CKEESEKC
