PA2BA_CRODU
ID PA2BA_CRODU Reviewed; 138 AA.
AC P24027; P0DJN2;
DT 01-MAR-1992, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-1992, sequence version 1.
DT 03-AUG-2022, entry version 114.
DE RecName: Full=Phospholipase A2 crotoxin basic chain CBa2;
DE Short=CB2;
DE Short=CTX subunit CBa2;
DE Short=svPLA2;
DE EC=3.1.1.4;
DE AltName: Full=Phosphatidylcholine 2-acylhydrolase;
DE Flags: Precursor;
OS Crotalus durissus terrificus (South American rattlesnake).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Lepidosauria; Squamata; Bifurcata; Unidentata; Episquamata; Toxicofera;
OC Serpentes; Colubroidea; Viperidae; Crotalinae; Crotalus.
OX NCBI_TaxID=8732;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Venom gland;
RX PubMed=2015302; DOI=10.1016/0167-4781(91)90132-6;
RA Bouchier C., Boulain J.-C., Bon C., Menez A.;
RT "Analysis of cDNAs encoding the two subunits of crotoxin, a phospholipase
RT A2 neurotoxin from rattlesnake venom: the acidic non enzymatic subunit
RT derives from a phospholipase A2-like precursor.";
RL Biochim. Biophys. Acta 1088:401-408(1991).
RN [2]
RP PROTEIN SEQUENCE OF 17-49, AND MASS SPECTROMETRY.
RC TISSUE=Venom;
RX PubMed=8033889; DOI=10.1111/j.1432-1033.1994.tb18978.x;
RA Faure G., Choumet V., Bouchier C., Camoin L., Guillaume J.-L., Monegier B.,
RA Vuilhorgne M., Bon C.;
RT "The origin of the diversity of crotoxin isoforms in the venom of Crotalus
RT durissus terrificus.";
RL Eur. J. Biochem. 223:161-164(1994).
RN [3]
RP PROTEIN SEQUENCE OF 17-39, FUNCTION, AND MASS SPECTROMETRY.
RC TISSUE=Venom;
RX PubMed=15032748; DOI=10.1042/bj20040125;
RA Chen Y.-H., Wang Y.-M., Hseu M.-J., Tsai I.-H.;
RT "Molecular evolution and structure-function relationships of crotoxin-like
RT and asparagine-6-containing phospholipases A2 in pit viper venoms.";
RL Biochem. J. 381:25-34(2004).
RN [4]
RP BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT, AND LETHAL DOSES.
RX PubMed=8513799; DOI=10.1111/j.1432-1033.1993.tb17946.x;
RA Faure G., Harvey A.L., Thomson E., Saliou B., Radvanyi F., Bon C.;
RT "Comparison of crotoxin isoforms reveals that stability of the complex
RT plays a major role in its pharmacological action.";
RL Eur. J. Biochem. 214:491-496(1993).
RN [5]
RP FUNCTION.
RX PubMed=8630095; DOI=10.1016/0006-2952(96)00097-4;
RA Donato N.J., Martin C.A., Perez M., Newman R.A., Vidal J.C., Etcheverry M.;
RT "Regulation of epidermal growth factor receptor activity by crotoxin, a
RT snake venom phospholipase A2 toxin. A novel growth inhibitory mechanism.";
RL Biochem. Pharmacol. 51:1535-1543(1996).
RN [6]
RP INHIBITION OF CROTOXIN BY CICS.
RX PubMed=10903514; DOI=10.1046/j.1432-1327.2000.01532.x;
RA Faure G., Villela C., Perales J., Bon C.;
RT "Interaction of the neurotoxic and nontoxic secretory phospholipases A2
RT with the crotoxin inhibitor from Crotalus serum.";
RL Eur. J. Biochem. 267:4799-4808(2000).
RN [7]
RP FUNCTION AS AN ANTICOAGULANT, SITE, AND 3D-STRUCTURE MODELING.
RX PubMed=18062812; DOI=10.1186/1472-6807-7-82;
RA Faure G., Gowda V.T., Maroun R.C.;
RT "Characterization of a human coagulation factor Xa-binding site on
RT Viperidae snake venom phospholipases A2 by affinity binding studies and
RT molecular bioinformatics.";
RL BMC Struct. Biol. 7:82-82(2007).
RN [8]
RP REVIEW.
RX PubMed=20109480; DOI=10.1016/j.toxicon.2010.01.011;
RA Sampaio S.C., Hyslop S., Fontes M.R., Prado-Franceschi J., Zambelli V.O.,
RA Magro A.J., Brigatte P., Gutierrez V.P., Cury Y.;
RT "Crotoxin: novel activities for a classic beta-neurotoxin.";
RL Toxicon 55:1045-1060(2010).
RN [9]
RP SITES.
RX PubMed=21787789; DOI=10.1016/j.jmb.2011.07.027;
RA Faure G., Xu H., Saul F.A.;
RT "Crystal structure of crotoxin reveals key residues involved in the
RT stability and toxicity of this potent heterodimeric beta-neurotoxin.";
RL J. Mol. Biol. 412:176-191(2011).
RN [10]
RP PHARMACEUTICAL, AND SUBUNIT.
RX PubMed=27241308; DOI=10.1016/j.jmb.2016.05.016;
RA Faure G., Bakouh N., Lourdel S., Odolczyk N., Premchandar A., Servel N.,
RA Hatton A., Ostrowski M.K., Xu H., Saul F.A., Moquereau C., Bitam S.,
RA Pranke I., Planelles G., Teulon J., Herrmann H., Roldan A.,
RA Zielenkiewicz P., Dadlez M., Lukacs G.L., Sermet-Gaudelus I., Ollero M.,
RA Corringer P.J., Edelman A.;
RT "Rattlesnake phospholipase A2 increases CFTR-chloride channel current and
RT corrects DelF508CFTR dysfunction: impact in cystic fibrosis.";
RL J. Mol. Biol. 428:2898-2915(2016).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.28 ANGSTROMS) OF 17-138, AND DISULFIDE BONDS.
RC TISSUE=Venom;
RX PubMed=18275084; DOI=10.1002/prot.21980;
RA Marchi-Salvador D.P., Correa L.C., Magro A.J., Oliveira C.Z., Soares A.M.,
RA Fontes M.R.;
RT "Insights into the role of oligomeric state on the biological activities of
RT crotoxin: crystal structure of a tetrameric phospholipase A2 formed by two
RT isoforms of crotoxin B from Crotalus durissus terrificus venom.";
RL Proteins 72:883-891(2008).
CC -!- FUNCTION: Heterodimer CA-CB: Crotoxin is a potent presynaptic
CC neurotoxin that possesses phospholipase A2 (PLA2) activity and exerts a
CC lethal action by blocking neuromuscular transmission. It consists of a
CC non-covalent association of a basic and weakly toxic PLA2 subunit
CC (CBa2, CBb, CBc, or CBd), with a small acidic, non-enzymatic and non-
CC toxic subunit (CA1, CA2, CA3 or CA4). The complex acts by binding to a
CC specific 48-kDa protein (R48) receptor located on presynaptic
CC membranes, forming a transient ternary complex CA-CB-R48, followed by
CC dissociation of the CA-CB complex and release of the CA subunit. At
CC equilibrium, only the CB subunits remain associated with the specific
CC crotoxin receptor. In addition to neurotoxicity, crotoxin has been
CC found to exert myotoxicity, nephrotoxicity, and cardiovascular toxicity
CC (PubMed:20109480). Moreover, anti-inflammatory, immunomodulatory, anti-
CC tumor and analgesic effects of crotoxin have also been reported
CC (PubMed:20109480). {ECO:0000269|PubMed:20109480}.
CC -!- FUNCTION: Monomer CBa2: The basic subunit of crotoxin is a snake venom
CC phospholipase A2 (PLA2) that exhibits weak neurotoxicity (10-fold less
CC than the heterodimer) and strong anticoagulant effects by binding to
CC factor Xa (F10) and inhibiting the prothrombinase activity (IC(50) is
CC 41 nM) (PubMed:18062812). In addition, it shows the same effects
CC described for the heterodimer and binds the nucleotide-binding domain
CC (NBD1) of CFTR chloride channels and increases the channel current
CC (PubMed:27241308). PLA2 catalyzes the calcium-dependent hydrolysis of
CC the 2-acyl groups in 3-sn-phosphoglycerides.
CC {ECO:0000269|PubMed:18062812, ECO:0000269|PubMed:27241308}.
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;
CC Evidence={ECO:0000250|UniProtKB:P62022};
CC Note=Binds 1 Ca(2+) ion. {ECO:0000250|UniProtKB:P62022};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.06 uM for 1-palmitoyl-2-(10-pyrenyldecanoyl)-sn-glycero-3-
CC monomethyl phosphatidic acid (monomer CBa2)
CC {ECO:0000269|PubMed:8513799};
CC KM=0.05 uM for 1-palmitoyl-2-(10-pyrenyldecanoyl)-sn-glycero-3-
CC monomethyl phosphatidic acid (class 2 heterodimer CA2-CBa2)
CC {ECO:0000269|PubMed:8513799};
CC KM=0.05 uM for 1-palmitoyl-2-(10-pyrenyldecanoyl)-sn-glycero-3-
CC monomethyl phosphatidic acid (class 2 heterodimer CA3-CBa2)
CC {ECO:0000269|PubMed:8513799};
CC Vmax=24 umol/min/mg enzyme (monomer CBa2)
CC {ECO:0000269|PubMed:8513799};
CC Vmax=25 umol/min/mg enzyme (class 2 heterodimer CA2-CBa2)
CC {ECO:0000269|PubMed:8513799};
CC Vmax=24 umol/min/mg enzyme (class 2 heterodimer CA3-CBa2)
CC {ECO:0000269|PubMed:8513799};
CC -!- SUBUNIT: Heterodimer of one of the acidic (CA1, CA2, CA3 or CA4) and
CC one of the basic (CBa1, CBa2, CBb, CBc or CBd) subunits; non-covalently
CC linked. The acidic subunit is non-toxic, without enzymatic activity and
CC comprises 3 peptides that are cross-linked by 5 disulfide bridges. The
CC basic subunit is toxic, has phospholipase A2 activity and is composed
CC of a single chain. Multiple variants of each subunit give different
CC crotoxin complexes that can be subdivided into 2 classes: (1) those of
CC high toxicity, low PLA2 activity (CBb, CBc and CBd linked with high
CC affinity to any CA) and high stability (K(d)=4.5 nM) and (2) those of
CC moderate toxicity, high PLA2 activity (CBa2 linked with low affinity to
CC any CA) and low stability (K(d)=25 nM). Interacts with human NBD1
CC domain of CFTR (PubMed:27241308). {ECO:0000269|PubMed:18275084,
CC ECO:0000269|PubMed:27241308, ECO:0000269|PubMed:8513799}.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC -!- MASS SPECTROMETRY: Mass=14245; Mass_error=1; Method=Electrospray;
CC Evidence={ECO:0000269|PubMed:8033889};
CC -!- MASS SPECTROMETRY: Mass=14244; Method=Electrospray;
CC Evidence={ECO:0000269|PubMed:15032748};
CC -!- TOXIC DOSE: In monomer CBa2, LD(50) is 700 ug/kg by intravenous
CC injection into mice. {ECO:0000269|PubMed:8513799}.
CC -!- TOXIC DOSE: In monomer CBa2, LD(50) is >3000 ug/kg by subcutaneous
CC injection into mice. {ECO:0000269|PubMed:8513799}.
CC -!- TOXIC DOSE: In class 2 heterodimer CA2-CBa2, LD(50) is 420 ug/kg by
CC intravenous injection into mice. {ECO:0000269|PubMed:8513799}.
CC -!- TOXIC DOSE: In class 2 heterodimer CA2-CBa2, LD(50) is 650 ug/kg by
CC subcutaneous injection into mice. {ECO:0000269|PubMed:8513799}.
CC -!- TOXIC DOSE: In class 2 heterodimer CA3-CBa2, LD(50) is 450 ug/kg by
CC intravenous injection into mice. {ECO:0000269|PubMed:8513799}.
CC -!- PHARMACEUTICAL: May be used to develop new agents to treat the most
CC common mutation of cystic fibrosis (DelF508CFTR). It shows a double
CC function: (i) as a potentiator, by increasing the chloride channel
CC current, and (ii) as a corrector, by permitting DelF508CFTR to escape
CC from the degradation pathway, facilitating its biosynthesis and
CC subsequent delivery to the plasma membrane.
CC {ECO:0000269|PubMed:27241308}.
CC -!- MISCELLANEOUS: The crotoxin heterodimer is inhibited by the crotoxin
CC inhibitor from Crotalus serum (CICS). CICS neutralizes the lethal
CC potency of crotoxin and inhibits its PLA2 activity. CICS only binds
CC tightly to the CB subunit and induces the dissociation of the
CC heterodimer (By similarity). Tested on the CA2-CBd heterodimer
CC (PubMed:10903514). {ECO:0000250, ECO:0000305|PubMed:10903514}.
CC -!- SIMILARITY: Belongs to the phospholipase A2 family. Group II subfamily.
CC D49 sub-subfamily. {ECO:0000305}.
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DR EMBL; X16100; CAA34227.1; -; mRNA.
DR PIR; S15068; PSRSB2.
DR PDB; 2QOG; X-ray; 2.28 A; A/D=17-138.
DR PDBsum; 2QOG; -.
DR AlphaFoldDB; P24027; -.
DR SMR; P24027; -.
DR BRENDA; 3.1.1.4; 1711.
DR SABIO-RK; P24027; -.
DR EvolutionaryTrace; P24027; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0099106; F:ion channel regulator activity; IEA:UniProtKB-KW.
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 Hydrolase; Ion channel impairing toxin; Lipid degradation;
KW Lipid metabolism; Metal-binding; Neurotoxin; Pharmaceutical;
KW Presynaptic neurotoxin; Secreted; Signal; Toxin.
FT SIGNAL 1..16
FT /evidence="ECO:0000269|PubMed:15032748,
FT ECO:0000269|PubMed:8033889"
FT CHAIN 17..138
FT /note="Phospholipase A2 crotoxin basic chain CBa2"
FT /id="PRO_0000022861"
FT ACT_SITE 63
FT /evidence="ECO:0000250|UniProtKB:P62022"
FT ACT_SITE 105
FT /evidence="ECO:0000250|UniProtKB:P62022"
FT BINDING 43
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P62022"
FT BINDING 45
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P62022"
FT BINDING 47
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P62022"
FT BINDING 64
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P62022"
FT SITE 17
FT /note="Responsible for the weak stability and toxicity"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 18
FT /note="Putative interfacial binding surface (IBS)"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 19
FT /note="Putative interfacial binding surface (IBS)"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 23
FT /note="Putative interfacial binding surface (IBS)"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 26
FT /note="Putative interfacial binding surface (IBS)"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 33
FT /note="Putative interfacial binding surface (IBS)"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 34
FT /note="Putative interfacial binding surface (IBS)"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 38
FT /note="Putative interfacial binding surface (IBS)"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 39
FT /note="Putative interfacial binding surface (IBS)"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 76
FT /note="Putative interfacial binding surface (IBS)"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 119
FT /note="Putative interfacial binding surface (IBS)"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 133
FT /note="Responsible for the reduced anticoagulant activity
FT (compared with CBc)"
FT /evidence="ECO:0000269|PubMed:18062812"
FT DISULFID 42..131
FT /evidence="ECO:0000269|PubMed:18275084,
FT ECO:0007744|PDB:2QOG"
FT DISULFID 44..60
FT /evidence="ECO:0000269|PubMed:18275084,
FT ECO:0007744|PDB:2QOG"
FT DISULFID 59..111
FT /evidence="ECO:0000269|PubMed:18275084,
FT ECO:0007744|PDB:2QOG"
FT DISULFID 65..138
FT /evidence="ECO:0000269|PubMed:18275084,
FT ECO:0007744|PDB:2QOG"
FT DISULFID 66..104
FT /evidence="ECO:0000269|PubMed:18275084,
FT ECO:0007744|PDB:2QOG"
FT DISULFID 73..97
FT /evidence="ECO:0000269|PubMed:18275084,
FT ECO:0007744|PDB:2QOG"
FT DISULFID 91..102
FT /evidence="ECO:0000269|PubMed:18275084,
FT ECO:0007744|PDB:2QOG"
FT CONFLICT 34
FT /note="V -> I (in Ref. 3; AA sequence)"
FT /evidence="ECO:0000305"
FT HELIX 19..29
FT /evidence="ECO:0007829|PDB:2QOG"
FT HELIX 33..36
FT /evidence="ECO:0007829|PDB:2QOG"
FT TURN 37..39
FT /evidence="ECO:0007829|PDB:2QOG"
FT TURN 41..43
FT /evidence="ECO:0007829|PDB:2QOG"
FT HELIX 55..69
FT /evidence="ECO:0007829|PDB:2QOG"
FT HELIX 71..73
FT /evidence="ECO:0007829|PDB:2QOG"
FT STRAND 82..85
FT /evidence="ECO:0007829|PDB:2QOG"
FT STRAND 88..91
FT /evidence="ECO:0007829|PDB:2QOG"
FT HELIX 96..114
FT /evidence="ECO:0007829|PDB:2QOG"
FT HELIX 115..117
FT /evidence="ECO:0007829|PDB:2QOG"
FT HELIX 121..123
FT /evidence="ECO:0007829|PDB:2QOG"
FT HELIX 128..131
FT /evidence="ECO:0007829|PDB:2QOG"
SQ SEQUENCE 138 AA; 15969 MW; 935D12258D47B058 CRC64;
MRALWIVAVL LVGVEGSLLQ FNKMIKFETR KNAVPFYAFY GCYCGWGGQG RPKDATDRCC
FVHDCCYGKL AKCNTKWDIY RYSLKSGYIT CGKGTWCKEQ ICECDRVAAE CLRRSLSTYK
NEYMFYPDSR CREPSETC
