PA2B2_BOTJR
ID PA2B2_BOTJR Reviewed; 138 AA.
AC P45881; Q6EMI4;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1995, sequence version 1.
DT 03-AUG-2022, entry version 113.
DE RecName: Full=Basic phospholipase A2 homolog bothropstoxin-II {ECO:0000303|PubMed:1660822, ECO:0000303|PubMed:9619591};
DE Short=Bothropstoxin II {ECO:0000303|PubMed:15134836};
DE Short=BthTX-II {ECO:0000303|PubMed:15134836, ECO:0000303|PubMed:1660822, ECO:0000303|PubMed:9619591};
DE Short=BtxtxII;
DE Short=svPLA2 homolog;
DE AltName: Full=BJU-PLA2 {ECO:0000305|PubMed:7666446};
DE Short=BJUPLA2 {ECO:0000303|PubMed:7666446};
DE AltName: Full=BOJU-II {ECO:0000303|PubMed:15134836};
DE AltName: Full=Myotoxic phospholipase A2;
DE Flags: Precursor;
OS Bothrops jararacussu (Jararacussu).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Lepidosauria; Squamata; Bifurcata; Unidentata; Episquamata; Toxicofera;
OC Serpentes; Colubroidea; Viperidae; Crotalinae; Bothrops.
OX NCBI_TaxID=8726;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Venom gland;
RX PubMed=7666446; DOI=10.1007/bf00170670;
RA Moura da Silva A.M., Paine M.J.I., Diniz M.R.D., Theakston R.D.G.,
RA Crampton J.M.;
RT "The molecular cloning of a phospholipase A2 from Bothrops jararacussu
RT snake venom: evolution of venom group II phospholipase A2's may imply gene
RT duplications.";
RL J. Mol. Evol. 41:174-179(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Venom gland;
RX PubMed=15134836; DOI=10.1016/j.biochi.2004.02.002;
RA Kashima S., Roberto P.G., Soares A.M., Astolfi-Filho S., Pereira J.O.,
RA Giuliati S., Faria M. Jr., Xavier M.A.S., Fontes M.R.M., Giglio J.R.,
RA Franca S.C.;
RT "Analysis of Bothrops jararacussu venomous gland transcriptome focusing on
RT structural and functional aspects: I -- gene expression profile of highly
RT expressed phospholipases A2.";
RL Biochimie 86:211-219(2004).
RN [3]
RP PROTEIN SEQUENCE OF 17-138, FUNCTION, AND SUBCELLULAR LOCATION.
RC TISSUE=Venom;
RX PubMed=9619591; DOI=10.1023/a:1022563401413;
RA Pereira M.F., Novello J.C., Cintra A.C., Giglio J.R., Landucci E.T.,
RA Oliveira B., Marangoni S.;
RT "The amino acid sequence of bothropstoxin-II, an Asp-49 myotoxin from
RT Bothrops jararacussu (Jararacucu) venom with low phospholipase A2
RT activity.";
RL J. Protein Chem. 17:381-386(1998).
RN [4]
RP FUNCTION, AND BIOASSAY.
RX PubMed=1660822; DOI=10.1016/0014-4800(91)90002-f;
RA Gutierrez J.M., Nunez J., Diaz C., Cintra A.C., Homsi-Brandeburgo M.I.,
RA Giglio J.R.;
RT "Skeletal muscle degeneration and regeneration after injection of
RT bothropstoxin-II, a phospholipase A2 isolated from the venom of the snake
RT Bothrops jararacussu.";
RL Exp. Mol. Pathol. 55:217-229(1991).
RN [5]
RP FUNCTION, BIOASSAY, AND TOXIC DOSE.
RC TISSUE=Venom;
RX PubMed=11018293; DOI=10.1016/s0300-9084(00)01150-0;
RA Andriao-Escarso S.H., Soares A.M., Rodrigues V.M., Angulo Y., Diaz C.,
RA Lomonte B., Gutierrez J.M., Giglio J.R.;
RT "Myotoxic phospholipases A(2) in bothrops snake venoms: effect of chemical
RT modifications on the enzymatic and pharmacological properties of
RT bothropstoxins from Bothrops jararacussu.";
RL Biochimie 82:755-763(2000).
RN [6]
RP PHARMACEUTICAL.
RX PubMed=29253818; DOI=10.1016/j.intimp.2017.12.012;
RA de Barros N.B., Aragao Macedo S.R., Ferreira A.S., Tagliari M.P.,
RA Kayano A.M., Nicolete L.D.F., Soares A.M., Nicolete R.;
RT "Asp49-phospholipase A2-loaded liposomes as experimental therapy in
RT cutaneous leishmaniasis model.";
RL Int. Immunopharmacol. 55:128-132(2018).
RN [7] {ECO:0000312|PDB:2OQD}
RP X-RAY CRYSTALLOGRAPHY (2.19 ANGSTROMS) OF 17-138, AND DISULFIDE BONDS.
RC TISSUE=Venom;
RX PubMed=18261474; DOI=10.1016/j.bbapap.2008.01.007;
RA Correa L.C., Marchi-Salvador D.P., Cintra A.C., Sampaio S.V., Soares A.M.,
RA Fontes M.R.;
RT "Crystal structure of a myotoxic Asp49-phospholipase A2 with low catalytic
RT activity: insights into Ca2+-independent catalytic mechanism.";
RL Biochim. Biophys. Acta 1784:591-599(2008).
RN [8] {ECO:0000312|PDB:3JR8}
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 17-138, SUBUNIT, AND DISULFIDE
RP BONDS.
RX PubMed=20878713; DOI=10.1002/prot.22858;
RA dos Santos J.I., Cintra-Francischinelli M., Borges R.J., Fernandes C.A.,
RA Pizzo P., Cintra A.C., Braz A.S., Soares A.M., Fontes M.R.;
RT "Structural, functional, and bioinformatics studies reveal a new snake
RT venom homologue phospholipase A(2) class.";
RL Proteins 79:61-78(2011).
CC -!- FUNCTION: Snake venom phospholipase A2 (PLA2) that shows low enzymatic
CC activity even tough it conserves the catalytic residues
CC (PubMed:9619591). Shows a strong myotoxic activity and induces indirect
CC hemolysis, anticoagulant properties, and cytotoxic activities
CC (PubMed:11018293). In vivo, it induces muscle necrosis, accompanied by
CC polymorphonuclear cell infiltration, and edema in the mouse paw
CC (PubMed:1660822, PubMed:11018293). It exerts its function even in the
CC absence of extracellular calcium, indicating it is not a calcium-
CC dependent enzyme (PubMed:20878713). A model of myotoxic mechanism has
CC been proposed: an apo Lys49-PLA2 is activated by the entrance of a
CC hydrophobic molecule (e.g. fatty acid) at the hydrophobic channel of
CC the protein leading to a reorientation of a monomer (By similarity).
CC This reorientation causes a transition between 'inactive' to 'active'
CC states, causing alignment of C-terminal and membrane-docking sites
CC (MDoS) side-by-side and putting the membrane-disruption sites (MDiS) in
CC the same plane, exposed to solvent and in a symmetric position for both
CC monomers (By similarity). The MDoS region stabilizes the toxin on
CC membrane by the interaction of charged residues with phospholipid head
CC groups (By similarity). Subsequently, the MDiS region destabilizes the
CC membrane with penetration of hydrophobic residues (By similarity). This
CC insertion causes a disorganization of the membrane, allowing an
CC uncontrolled influx of ions (i.e. calcium and sodium), and eventually
CC triggering irreversible intracellular alterations and cell death (By
CC similarity). {ECO:0000250|UniProtKB:I6L8L6,
CC ECO:0000269|PubMed:11018293, ECO:0000269|PubMed:20878713,
CC ECO:0000269|PubMed:9619591}.
CC -!- SUBUNIT: Homodimer; non-covalently linked (probable alternative/compact
CC dimer conformation). {ECO:0000269|PubMed:20878713}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:9619591}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:9619591}.
CC -!- TOXIC DOSE: LD(50) is 7.0 mg/kg by intraperitoneal injection into mice.
CC {ECO:0000269|PubMed:11018293}.
CC -!- PHARMACEUTICAL: Has been tested as therapy in mice cutaneous
CC leishmaniasis model. Incorporated in liposomes, it is able to decrease
CC the size of the mice paw injury and induce a marked inhibition for
CC Leishmania amazonensis amastigotes in lymph node and paw tissues. It
CC also induces the production of inflammatory mediators, such as TNF-
CC alpha and nitric oxid (NO), that probably are responsible of the
CC leishmaniasis infection decrease. {ECO:0000269|PubMed:29253818}.
CC -!- SIMILARITY: Belongs to the phospholipase A2 family. Group II subfamily.
CC D49 sub-subfamily. {ECO:0000305}.
CC -!- CAUTION: Shows no or low enzymatic activity even tough it conserves the
CC catalytic residues. This may be due to the distorsion of the calcium
CC binding loop. {ECO:0000305|PubMed:20878713}.
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DR EMBL; X76289; CAA53921.1; -; mRNA.
DR EMBL; AY185201; AAO27454.1; -; mRNA.
DR PIR; I50098; I50098.
DR PDB; 2OQD; X-ray; 2.19 A; A/B=17-138.
DR PDB; 3JR8; X-ray; 2.10 A; A/B=17-138.
DR PDBsum; 2OQD; -.
DR PDBsum; 3JR8; -.
DR AlphaFoldDB; P45881; -.
DR SMR; P45881; -.
DR ABCD; P45881; 5 sequenced antibodies.
DR BRENDA; 3.1.1.4; 6809.
DR EvolutionaryTrace; P45881; -.
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:InterPro.
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.
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;
KW Direct protein sequencing; Disulfide bond; Hemostasis impairing toxin;
KW Myotoxin; Pharmaceutical; Secreted; Signal; Toxin.
FT SIGNAL 1..16
FT /evidence="ECO:0000269|PubMed:9619591"
FT CHAIN 17..138
FT /note="Basic phospholipase A2 homolog bothropstoxin-II"
FT /id="PRO_0000022821"
FT REGION 121..133
FT /note="Important for membrane-damaging activities in
FT eukaryotes and bacteria; heparin-binding"
FT /evidence="ECO:0000250|UniProtKB:P24605"
FT SITE 19
FT /note="Putative hydrophobic membrane-disrupting site
FT (MDiS)"
FT /evidence="ECO:0000250|UniProtKB:P20474"
FT SITE 26
FT /note="Putative hydrophobic membrane-disrupting site
FT (MDiS)"
FT /evidence="ECO:0000250|UniProtKB:P20474"
FT SITE 31
FT /note="Putative membrane-disrupting site (MDiS)"
FT /evidence="ECO:0000250|UniProtKB:P20474"
FT SITE 32
FT /note="Putative hydrophobic membrane-disrupting site
FT (MDiS)"
FT /evidence="ECO:0000250|UniProtKB:P20474"
FT SITE 79
FT /note="Putative cationic membrane-docking site (MDoS)"
FT /evidence="ECO:0000250|UniProtKB:P20474"
FT SITE 121
FT /note="Important residue of the cationic membrane-docking
FT site (MDoS)"
FT /evidence="ECO:0000250|UniProtKB:I6L8L6"
FT SITE 130
FT /note="Hydrophobic membrane-disruption site (MDiS)"
FT /evidence="ECO:0000250|UniProtKB:I6L8L6"
FT SITE 133
FT /note="Cationic membrane-docking site (MDoS)"
FT /evidence="ECO:0000250|UniProtKB:I6L8L6"
FT DISULFID 42..131
FT /evidence="ECO:0000269|PubMed:18261474,
FT ECO:0000269|PubMed:20878713, ECO:0007744|PDB:2OQD,
FT ECO:0007744|PDB:3JR8"
FT DISULFID 44..60
FT /evidence="ECO:0000269|PubMed:18261474,
FT ECO:0000269|PubMed:20878713, ECO:0007744|PDB:2OQD,
FT ECO:0007744|PDB:3JR8"
FT DISULFID 59..111
FT /evidence="ECO:0000269|PubMed:18261474,
FT ECO:0000269|PubMed:20878713, ECO:0007744|PDB:2OQD,
FT ECO:0007744|PDB:3JR8"
FT DISULFID 65..138
FT /evidence="ECO:0000269|PubMed:18261474,
FT ECO:0000269|PubMed:20878713, ECO:0007744|PDB:2OQD,
FT ECO:0007744|PDB:3JR8"
FT DISULFID 66..104
FT /evidence="ECO:0000269|PubMed:18261474,
FT ECO:0000269|PubMed:20878713, ECO:0007744|PDB:2OQD,
FT ECO:0007744|PDB:3JR8"
FT DISULFID 73..97
FT /evidence="ECO:0000269|PubMed:18261474,
FT ECO:0000269|PubMed:20878713, ECO:0007744|PDB:2OQD,
FT ECO:0007744|PDB:3JR8"
FT DISULFID 91..102
FT /evidence="ECO:0000269|PubMed:18261474,
FT ECO:0000269|PubMed:20878713, ECO:0007744|PDB:2OQD,
FT ECO:0007744|PDB:3JR8"
FT CONFLICT 21
FT /note="F -> W (in Ref. 3; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 49..55
FT /note="QGQPKDA -> RGKPVDP (in Ref. 3; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 68..77
FT /note="GKLTNCKPKT -> KVTNYCPKKN (in Ref. 3; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 85..99
FT /note="ENGVIICGEGTPCEK -> VSYNYCRGGPCDE (in Ref. 3; AA
FT sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 108
FT /note="A -> I (in Ref. 3; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 117
FT /note="R -> G (in Ref. 3; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 120..133
FT /note="KKRYMAYPDVLCKK -> NKKAYYHLKPFCKE (in Ref. 3; AA
FT sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 137
FT /note="K -> T (in Ref. 3; AA sequence)"
FT /evidence="ECO:0000305"
FT HELIX 18..29
FT /evidence="ECO:0007829|PDB:3JR8"
FT HELIX 33..36
FT /evidence="ECO:0007829|PDB:3JR8"
FT TURN 37..39
FT /evidence="ECO:0007829|PDB:3JR8"
FT TURN 41..48
FT /evidence="ECO:0007829|PDB:3JR8"
FT HELIX 55..68
FT /evidence="ECO:0007829|PDB:3JR8"
FT TURN 75..77
FT /evidence="ECO:0007829|PDB:3JR8"
FT HELIX 96..114
FT /evidence="ECO:0007829|PDB:3JR8"
FT HELIX 116..118
FT /evidence="ECO:0007829|PDB:3JR8"
FT HELIX 121..123
FT /evidence="ECO:0007829|PDB:3JR8"
FT HELIX 128..130
FT /evidence="ECO:0007829|PDB:3JR8"
SQ SEQUENCE 138 AA; 15765 MW; E93515551C5ED81A CRC64;
MRTLWIMAVL LVGVEGDLWQ FGQMILKETG KLPFPYYTTY GCYCGWGGQG QPKDATDRCC
FVHDCCYGKL TNCKPKTDRY SYSRENGVII CGEGTPCEKQ ICECDKAAAV CFRENLRTYK
KRYMAYPDVL CKKPAEKC
