PA2BB_CRODU
ID PA2BB_CRODU Reviewed; 122 AA.
AC P0CG56;
DT 28-NOV-2012, integrated into UniProtKB/Swiss-Prot.
DT 28-NOV-2012, sequence version 1.
DT 03-AUG-2022, entry version 28.
DE RecName: Full=Phospholipase A2 crotoxin basic subunit CBb;
DE Short=CTX subunit CBb;
DE Short=svPLA2;
DE EC=3.1.1.4;
DE AltName: Full=Phosphatidylcholine 2-acylhydrolase;
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 PROTEIN SEQUENCE, X-RAY CRYSTALLOGRAPHY (1.35 ANGSTROMS) IN COMPLEX WITH
RP CROTOXIN CA2 SUBUNIT, SITES, AND DISULFIDE BONDS.
RC TISSUE=Venom;
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 [2]
RP BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT, AND LETHAL DOSES.
RC TISSUE=Venom;
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 [3]
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 [4]
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 [5]
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 [6]
RP PHARMACEUTICAL.
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).
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 ECO:0000269|PubMed:8630095}.
CC -!- FUNCTION: Monomer CBb: 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. In
CC addition, it shows the same effects described for the heterodimer and
CC binds the nucleotide-binding domain (NBD1) of CFTR chloride channels
CC and increases the channel current (PubMed:27241308). PLA2 catalyzes the
CC calcium-dependent hydrolysis of the 2-acyl groups in 3-sn-
CC phosphoglycerides. {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 -!- 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=0.07 uM for 1-palmitoyl-2-(10-pyrenyldecanoyl)-sn-glycero-3-
CC monomethyl phosphatidic acid (monomer CBb)
CC {ECO:0000269|PubMed:8513799};
CC KM=0.3 uM for 1-palmitoyl-2-(10-pyrenyldecanoyl)-sn-glycero-3-
CC monomethyl phosphatidic acid (class 2 heterodimer CA2-CBb)
CC {ECO:0000269|PubMed:8513799};
CC KM=0.2 uM for 1-palmitoyl-2-(10-pyrenyldecanoyl)-sn-glycero-3-
CC monomethyl phosphatidic acid (class 2 heterodimer CA3-CBb)
CC {ECO:0000269|PubMed:8513799};
CC Vmax=22 umol/min/mg enzyme (monomer CBb)
CC {ECO:0000269|PubMed:8513799};
CC Vmax=10 umol/min/mg enzyme (class 2 heterodimer CA2-CBb)
CC {ECO:0000269|PubMed:8513799};
CC Vmax=9 umol/min/mg enzyme (class 2 heterodimer CA3-CBb)
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). {ECO:0000269|PubMed:21787789,
CC ECO:0000269|PubMed:8513799}.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC -!- TOXIC DOSE: In monomer CBb, LD(50) is 500 ug/kg by intravenous
CC injection into mice. {ECO:0000269|PubMed:8513799}.
CC -!- TOXIC DOSE: In class 1 heterodimer CA2-CBb, LD(50) is 110 ug/kg by
CC intravenous injection into mice. {ECO:0000269|PubMed:8513799}.
CC -!- TOXIC DOSE: In class 1 heterodimer CA3-CBb, LD(50) is 95 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:0000305|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 PDB; 3R0L; X-ray; 1.35 A; D=1-122.
DR PDBsum; 3R0L; -.
DR AlphaFoldDB; P0CG56; -.
DR SMR; P0CG56; -.
DR SABIO-RK; P0CG56; -.
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:InterPro.
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.
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; Metal-binding; Pharmaceutical;
KW Secreted; Toxin.
FT CHAIN 1..122
FT /note="Phospholipase A2 crotoxin basic subunit CBb"
FT /id="PRO_0000420455"
FT REGION 61..?
FT /note="Putative region that binds to the R48 receptor
FT (PubMed:21787789)"
FT /evidence="ECO:0000269|PubMed:21787789"
FT ACT_SITE 47
FT /evidence="ECO:0000250|UniProtKB:P62022"
FT ACT_SITE 89
FT /evidence="ECO:0000250|UniProtKB:P62022"
FT BINDING 27
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P62022"
FT BINDING 29
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P62022"
FT BINDING 31
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P62022"
FT BINDING 48
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P62022"
FT SITE 1
FT /note="Important for stability and high toxicity"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 2
FT /note="Putative interfacial binding surface (IBS)"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 3
FT /note="Putative interfacial binding surface (IBS)"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 7
FT /note="Putative interfacial binding surface (IBS)"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 10
FT /note="Putative interfacial binding surface (IBS)"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 14
FT /note="Binds Q-49 of CBa2"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 16
FT /note="Binds G-45 of CBa2"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 17
FT /note="Putative interfacial binding surface (IBS)"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 18
FT /note="Binds G-45 of CBa2"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 18
FT /note="Binds Y-43 of CBa2"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 18
FT /note="Putative interfacial binding surface (IBS)"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 22
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 30
FT /note="Binds D-105 of CBa2, important for stability (T-31)"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 31
FT /note="Binds E-93 of CBa2"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 60
FT /note="Putative interfacial binding surface (IBS)"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 61
FT /note="Binds D-95 of CBa2, important for stability (T-70)"
FT /evidence="ECO:0000269|PubMed:21787789"
FT SITE 103
FT /note="Putative interfacial binding surface (IBS)"
FT /evidence="ECO:0000269|PubMed:21787789"
FT DISULFID 26..115
FT /evidence="ECO:0000269|PubMed:21787789,
FT ECO:0007744|PDB:3R0L"
FT DISULFID 28..44
FT /evidence="ECO:0000269|PubMed:21787789,
FT ECO:0007744|PDB:3R0L"
FT DISULFID 43..95
FT /evidence="ECO:0000269|PubMed:21787789,
FT ECO:0007744|PDB:3R0L"
FT DISULFID 49..122
FT /evidence="ECO:0000269|PubMed:21787789,
FT ECO:0007744|PDB:3R0L"
FT DISULFID 50..88
FT /evidence="ECO:0000269|PubMed:21787789,
FT ECO:0007744|PDB:3R0L"
FT DISULFID 57..81
FT /evidence="ECO:0000269|PubMed:21787789,
FT ECO:0007744|PDB:3R0L"
FT DISULFID 75..86
FT /evidence="ECO:0000269|PubMed:21787789,
FT ECO:0007744|PDB:3R0L"
FT HELIX 2..13
FT /evidence="ECO:0007829|PDB:3R0L"
FT HELIX 17..20
FT /evidence="ECO:0007829|PDB:3R0L"
FT TURN 25..27
FT /evidence="ECO:0007829|PDB:3R0L"
FT STRAND 28..30
FT /evidence="ECO:0007829|PDB:3R0L"
FT HELIX 39..52
FT /evidence="ECO:0007829|PDB:3R0L"
FT TURN 53..56
FT /evidence="ECO:0007829|PDB:3R0L"
FT TURN 59..61
FT /evidence="ECO:0007829|PDB:3R0L"
FT STRAND 66..68
FT /evidence="ECO:0007829|PDB:3R0L"
FT STRAND 70..75
FT /evidence="ECO:0007829|PDB:3R0L"
FT HELIX 80..98
FT /evidence="ECO:0007829|PDB:3R0L"
FT HELIX 100..102
FT /evidence="ECO:0007829|PDB:3R0L"
FT HELIX 105..107
FT /evidence="ECO:0007829|PDB:3R0L"
FT HELIX 112..114
FT /evidence="ECO:0007829|PDB:3R0L"
SQ SEQUENCE 122 AA; 14167 MW; D574F332898AF53A CRC64;
HLLQFNKMIK FETRKNAVPF YAFYGCYCGW GGQGRPKDAT DRCCFVHDCC YGKLAKCNTK
WDIYRYSLKS GYITCGKGTW CEEQICECDR VAAECLRRSL STYKNGYMFY PDSRCRGPSE
TC
