PA2BC_CRODU
ID PA2BC_CRODU Reviewed; 138 AA.
AC P62022; P07517; P23559;
DT 01-APR-1988, integrated into UniProtKB/Swiss-Prot.
DT 07-JUN-2004, sequence version 1.
DT 03-AUG-2022, entry version 88.
DE RecName: Full=Phospholipase A2 crotoxin basic subunit CBc;
DE Short=CB1;
DE Short=CTX subunit CBc;
DE Short=svPLA2;
DE EC=3.1.1.4 {ECO:0000255|PROSITE-ProRule:PRU10035, ECO:0000255|PROSITE-ProRule:PRU10036};
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], AND TISSUE SPECIFICITY.
RC TISSUE=Venom gland;
RX PubMed=3174444; DOI=10.1093/nar/16.18.9050;
RA Ducancel F., Guignery Frelat G., Menez A., Boulain J.-C., Bouchier C.,
RA Bon C.;
RT "Cloning and sequencing of cDNAs encoding the two subunits of Crotoxin.";
RL Nucleic Acids Res. 16:9050-9050(1988).
RN [2]
RP PROTEIN SEQUENCE OF 17-49, MASS SPECTROMETRY, AND SUBCELLULAR LOCATION.
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, SUBUNIT, 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 PHARMACEUTICAL.
RX PubMed=11948110;
RA Cura J.E., Blanzaco D.P., Brisson C., Cura M.A., Cabrol R., Larrateguy L.,
RA Mendez C., Sechi J.C., Silveira J.S., Theiller E., de Roodt A.R.,
RA Vidal J.C.;
RT "Phase I and pharmacokinetics study of crotoxin (cytotoxic PLA(2), NSC-
RT 624244) in patients with advanced cancer.";
RL Clin. Cancer Res. 8:1033-1041(2002).
RN [8]
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 [9]
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 [10]
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 [11]
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 [12]
RP PHARMACEUTICAL.
RX PubMed=30862840; DOI=10.1038/s41598-019-40903-0;
RA de Araujo Pimenta L., de Almeida M.E.S., Bretones M.L., Cirillo M.C.,
RA Curi R., Sampaio S.C.;
RT "Crotoxin promotes macrophage reprogramming towards an antiangiogenic
RT phenotype.";
RL Sci. Rep. 9:4281-4281(2019).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (2.28 ANGSTROMS) OF 17-138 IN COMPLEX WITH CALCIUM
RP ION, COFACTOR, 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 (By similarity).
CC It consists of a non-covalent association of a basic and weakly toxic
CC PLA2 subunit (CBa2, CBb, CBc, or CBd), with a small acidic, non-
CC enzymatic and non-toxic subunit (CA1, CA2, CA3 or CA4) (By similarity).
CC The complex acts by binding to a specific 48-kDa protein (R48) receptor
CC located on presynaptic membranes, forming a transient ternary complex
CC CA-CB-R48, followed by dissociation of the CA-CB complex and release of
CC the CA subunit (By similarity). At equilibrium, only the CB subunits
CC remain associated with the specific crotoxin receptor (By similarity).
CC In addition to neurotoxicity, crotoxin has been found to exert
CC 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:0000250|UniProtKB:C0HM14,
CC ECO:0000269|PubMed:20109480}.
CC -!- FUNCTION: Monomer CBc: 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 very strong anticoagulant effects by binding
CC to factor Xa (F10) and inhibiting the prothrombinase activity (IC(50)
CC is 0.7 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:0000269|PubMed:18275084};
CC Note=Binds 1 Ca(2+) ion. {ECO:0000269|PubMed:18275084};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.07 uM for 1-palmitoyl-2-(10-pyrenyldecanoyl)-sn-glycero-3-
CC monomethyl phosphatidic acid (monomer CBc)
CC {ECO:0000269|PubMed:8513799};
CC KM=0.22 uM for 1-palmitoyl-2-(10-pyrenyldecanoyl)-sn-glycero-3-
CC monomethyl phosphatidic acid (class 1 heterodimer CA2-CBc)
CC {ECO:0000269|PubMed:8513799};
CC KM=0.2 uM for 1-palmitoyl-2-(10-pyrenyldecanoyl)-sn-glycero-3-
CC monomethyl phosphatidic acid (class 1 heterodimer CA3-CBc)
CC {ECO:0000269|PubMed:8513799};
CC Vmax=18 umol/min/mg enzyme (monomer CBc)
CC {ECO:0000269|PubMed:8513799};
CC Vmax=7 umol/min/mg enzyme (class 1 heterodimer CA2-CBc)
CC {ECO:0000269|PubMed:8513799};
CC Vmax=6.6 umol/min/mg enzyme (class 1 heterodimer CA3-CBc)
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:15032748,
CC ECO:0000269|PubMed:18275084, ECO:0000269|PubMed:27241308,
CC ECO:0000269|PubMed:8513799}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:8033889}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000269|PubMed:3174444}.
CC -!- MASS SPECTROMETRY: Mass=14186; Mass_error=0.9; Method=Electrospray;
CC Evidence={ECO:0000269|PubMed:8033889};
CC -!- MASS SPECTROMETRY: Mass=14183; Method=Electrospray;
CC Evidence={ECO:0000269|PubMed:15032748};
CC -!- TOXIC DOSE: In monomer CBc, LD(50) is 480 ug/kg by intravenous
CC injection into mice. {ECO:0000269|PubMed:8513799}.
CC -!- TOXIC DOSE: In class 1 heterodimer CA2-CBc, LD(50) is 80 ug/kg by
CC intravenous injection into mice. {ECO:0000269|PubMed:8513799}.
CC -!- TOXIC DOSE: In class 1 heterodimer CA3-CBc, LD(50) is 110 ug/kg by
CC intravenous injection into mice. {ECO:0000269|PubMed:8513799}.
CC -!- PHARMACEUTICAL: Crotoxin (CA-CBc) is under phase I clinical trial as an
CC anti-tumor drug. It has been shown to induce neurotoxic tolerance in
CC animals allowing them to receive high doses associated with effective
CC anti-tumor activity in the absence of adverse side effects.
CC {ECO:0000305|PubMed:30862840}.
CC -!- PHARMACEUTICAL: May be used to develop new agents to treat the most
CC common mutation of cystic fibrosis (PHE-508 DEL). It shows a double
CC function: (i) as a potentiator, by increasing the chloride channel
CC current, and (ii) as a corrector, by permitting PHE-508 DEL 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|UniProtKB:C0HM14,
CC 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; X12603; CAA31123.1; -; mRNA.
DR PIR; S02257; PSRSBT.
DR PDB; 2QOG; X-ray; 2.28 A; B/C=17-138.
DR PDBsum; 2QOG; -.
DR AlphaFoldDB; P62022; -.
DR SMR; P62022; -.
DR ABCD; P62022; 7 sequenced antibodies.
DR SABIO-RK; P62022; -.
DR EvolutionaryTrace; P62022; -.
DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
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:0044398; P:envenomation resulting in induction of edema in another organism; IDA:UniProtKB.
DR GO; GO:0044534; P:envenomation resulting in modulation of apoptotic process in another organism; IDA:UniProtKB.
DR GO; GO:0044521; P:envenomation resulting in muscle damage in another organism; IDA:UniProtKB.
DR GO; GO:0044478; P:envenomation resulting in positive regulation of platelet aggregation in another organism; IDA:UniProtKB.
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 subunit CBc"
FT /id="PRO_0000022859"
FT ACT_SITE 63
FT /evidence="ECO:0000305|PubMed:18275084"
FT ACT_SITE 105
FT /evidence="ECO:0000305|PubMed:18275084"
FT BINDING 43
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:18275084,
FT ECO:0007744|PDB:2QOG"
FT BINDING 45
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:18275084,
FT ECO:0007744|PDB:2QOG"
FT BINDING 47
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:18275084,
FT ECO:0007744|PDB:2QOG"
FT BINDING 64
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000269|PubMed:18275084,
FT ECO:0007744|PDB:2QOG"
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 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 higher anticoagulant activity
FT (compared with CBa2)"
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 HELIX 18..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 STRAND 44..47
FT /evidence="ECO:0007829|PDB:2QOG"
FT HELIX 55..68
FT /evidence="ECO:0007829|PDB:2QOG"
FT TURN 69..72
FT /evidence="ECO:0007829|PDB:2QOG"
FT TURN 75..77
FT /evidence="ECO:0007829|PDB:2QOG"
FT HELIX 96..114
FT /evidence="ECO:0007829|PDB:2QOG"
FT HELIX 116..118
FT /evidence="ECO:0007829|PDB:2QOG"
FT HELIX 121..123
FT /evidence="ECO:0007829|PDB:2QOG"
FT TURN 128..130
FT /evidence="ECO:0007829|PDB:2QOG"
SQ SEQUENCE 138 AA; 15907 MW; 84A118931DFFE2E3 CRC64;
MRALWIVAVL LVGVEGHLLQ FNKMIKFETR KNAIPFYAFY GCYCGWGGRG RPKDATDRCC
FVHDCCYGKL AKCNTKWDIY PYSLKSGYIT CGKGTWCEEQ ICECDRVAAE CLRRSLSTYK
YGYMFYPDSR CRGPSETC
