PA2H1_BOTMO
ID PA2H1_BOTMO Reviewed; 138 AA.
AC P82114; A0A1S5XW05;
DT 16-NOV-2001, integrated into UniProtKB/Swiss-Prot.
DT 25-MAY-2022, sequence version 2.
DT 03-AUG-2022, entry version 91.
DE RecName: Full=Basic phospholipase A2 homolog MjTX-I {ECO:0000303|PubMed:23573271, ECO:0000303|PubMed:29985425};
DE AltName: Full=Basic phospholipase A2 homolog 1;
DE Short=svPLA2 homolog;
DE AltName: Full=Basic phospholipase A2 homolog BomoTx {ECO:0000303|PubMed:28265084};
DE AltName: Full=Myotoxin I {ECO:0000303|PubMed:10620318};
DE Flags: Precursor;
OS Bothrops moojeni (Lance-headed viper) (Caissaca).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Lepidosauria; Squamata; Bifurcata; Unidentata; Episquamata; Toxicofera;
OC Serpentes; Colubroidea; Viperidae; Crotalinae; Bothrops.
OX NCBI_TaxID=98334;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, AND MASS
RP SPECTROMETRY.
RC TISSUE=Venom, and Venom gland;
RX PubMed=28265084; DOI=10.1073/pnas.1615484114;
RA Zhang C., Medzihradszky K.F., Sanchez E.E., Basbaum A.I., Julius D.;
RT "Lys49 myotoxin from the Brazilian lancehead pit viper elicits pain through
RT regulated ATP release.";
RL Proc. Natl. Acad. Sci. U.S.A. 114:E2524-E2532(2017).
RN [2]
RP PROTEIN SEQUENCE OF 17-138, FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, AND
RP TOXIC DOSE.
RC TISSUE=Venom;
RX PubMed=10620318; DOI=10.1006/abbi.1999.1492;
RA Soares A.M., Andriao-Escarso S.H., Augulo Y., Lomonte B., Gutierrez J.M.,
RA Marangoni S., Toyama M.H., Arni R.K., Giglio J.R.;
RT "Structural and functional characterization of myotoxin I, a Lys49
RT phospholipase A2 homolog from Bothrops moojeni (Caissaca) snake venom.";
RL Arch. Biochem. Biophys. 373:7-15(2000).
RN [3]
RP CRYSTALLIZATION, AND SUBUNIT.
RX PubMed=16511185; DOI=10.1107/s174430910502717x;
RA Marchi-Salvador D.P., Silveira L.B., Soares A.M., Fontes M.R.;
RT "Crystallization and preliminary X-ray diffraction analysis of myotoxin I,
RT a Lys49-phospholipase A2 from Bothrops moojeni.";
RL Acta Crystallogr. F 61:882-884(2005).
RN [4] {ECO:0000312|PDB:3T0R}
RP X-RAY CRYSTALLOGRAPHY (2.49 ANGSTROMS) OF 17-138, FUNCTION, SUBUNIT, AND
RP DISULFIDE BOND.
RC TISSUE=Venom;
RX PubMed=23573271; DOI=10.1371/journal.pone.0060610;
RA Salvador G.H.M., Fernandes C.A., Magro A.J., Marchi-Salvador D.P.,
RA Cavalcante W.L.G., Fernandez R.M., Gallacci M., Soares A.M., Oliveira C.L.,
RA Fontes M.R.M.;
RT "Structural and phylogenetic studies with MjTX-I reveal a multi-oligomeric
RT toxin--a novel feature in Lys49-PLA2s protein class.";
RL PLoS ONE 8:E60610-E60610(2013).
RN [5] {ECO:0000312|PDB:6CE2}
RP X-RAY CRYSTALLOGRAPHY (2.15 ANGSTROMS) OF 17-138 IN COMPLEX WITH SURAMIN,
RP ACTIVITY REGULATION, AND DISULFIDE BOND.
RX PubMed=29985425; DOI=10.1038/s41598-018-28584-7;
RA Salvador G.H.M., Dreyer T.R., Gomes A.A.S., Cavalcante W.L.G.,
RA Dos Santos J.I., Gandin C.A., de Oliveira Neto M., Gallacci M.,
RA Fontes M.R.M.;
RT "Structural and functional characterization of suramin-bound MjTX-I from
RT Bothrops moojeni suggests a particular myotoxic mechanism.";
RL Sci. Rep. 8:10317-10317(2018).
RN [6] {ECO:0000312|PDB:7LYE}
RP X-RAY CRYSTALLOGRAPHY (1.76 ANGSTROMS) OF 17-138 IN COMPLEX WITH PLA2
RP INHIBITOR VARESPLADIB, SEQUENCE REVISION TO 35; 83; 94; 116; 117; 124; 126;
RP 135; 137, PARTIAL PROTEIN SEQUENCE, FUNCTION, BIOASSAY, SUBCELLULAR
RP LOCATION, AND DISULFIDE BOND.
RC TISSUE=Venom;
RX PubMed=33865953; DOI=10.1016/j.bbagen.2021.129913;
RA Salvador G.H.M., Borges R.J., Lomonte B., Lewin M.R., Fontes M.R.M.;
RT "The synthetic varespladib molecule is a multi-functional inhibitor for
RT PLA2 and PLA2-like ophidic toxins.";
RL Biochim. Biophys. Acta 1865:129913-129913(2021).
CC -!- FUNCTION: Snake venom phospholipase A2 homolog that lacks enzymatic
CC activity (PubMed:28265084). In vivo, it displays local myotoxin and
CC edema-inducing activities and is lethal by intraperitoneal injection
CC (PubMed:10620318, PubMed:33865953). The myotoxicity effect is weaker in
CC comparison to other myotoxins, probably due to the formation of high
CC molecular weight complexes and to the oligomeric conformation
CC (conventional dimer) (PubMed:10620318, PubMed:23573271). It shows
CC specificity toward neurons and myotubes, but not on a variety of other
CC cell types (PubMed:28265084, PubMed:10620318). This PLA2 excites a
CC cohort of sensory neurons via ATP release and consequent activation of
CC P2RX2 and/or P2RX3 purinergic receptors (PubMed:28265084). Pannexin
CC hemichannels act as downstream mediators of toxin-evoked ATP release
CC (PubMed:28265084). In vivo, it elicits nonneurogenic inflammatory pain,
CC thermal hyperalgesia, and mechanical allodynia, of which the latter is
CC completely dependent on purinergic signaling (PubMed:28265084).
CC {ECO:0000269|PubMed:10620318, ECO:0000269|PubMed:23573271,
CC ECO:0000269|PubMed:28265084, ECO:0000269|PubMed:33865953}.
CC -!- ACTIVITY REGULATION: Myotoxin activity is inhibited by suramin and
CC varespladib (PubMed:29985425, PubMed:33865953). Inhibition by suramin
CC may be caused by (i) distortion of MDiS from both monomers impairing
CC the membrane disruption mechanism by the toxin and (ii) surface
CC electrostatic changes of the complex that interfere with the toxin
CC membrane dockage process (putative-MDoS is partially hidden)
CC (PubMed:29985425). Inhibition by varespladib is probably through
CC varespladib binding to MDoS (PubMed:33865953).
CC {ECO:0000269|PubMed:29985425, ECO:0000269|PubMed:33865953}.
CC -!- SUBUNIT: Monomer in solution (PubMed:29985425). Homodimer; non-
CC covalently linked (probable conventional/extended dimer conformation)
CC (PubMed:10620318, PubMed:23573271). Homotetramer (dimer of homodimer
CC (probable conventional/extended dimer conformation)); non-covalently
CC linked (PubMed:16511185, PubMed:23573271). Homooligomer
CC (PubMed:10620318, PubMed:23573271). {ECO:0000269|PubMed:10620318,
CC ECO:0000269|PubMed:23573271, ECO:0000269|PubMed:29985425,
CC ECO:0000305|PubMed:16511185}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:10620318}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:10620318}.
CC -!- MASS SPECTROMETRY: Mass=13835; Method=MALDI;
CC Evidence={ECO:0000269|PubMed:28265084};
CC -!- TOXIC DOSE: LD(50) is 8.5 mg/kg by intraperitoneal injection into mice.
CC {ECO:0000269|PubMed:10620318}.
CC -!- SIMILARITY: Belongs to the phospholipase A2 family. Group II subfamily.
CC K49 sub-subfamily. {ECO:0000305}.
CC -!- CAUTION: Does not bind calcium as one of the calcium-binding sites is
CC lost (Asp->Lys in position 64, which corresponds to 'Lys-49' in the
CC current nomenclature). {ECO:0000305}.
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DR EMBL; KX856005; AQQ72931.1; -; mRNA.
DR PDB; 3T0R; X-ray; 2.49 A; A/B/C/D=1-121.
DR PDB; 6CE2; X-ray; 2.15 A; A/B=1-121.
DR PDB; 7LYE; X-ray; 1.76 A; A/B/C/D=1-121.
DR PDBsum; 3T0R; -.
DR PDBsum; 6CE2; -.
DR PDBsum; 7LYE; -.
DR AlphaFoldDB; P82114; -.
DR SMR; P82114; -.
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; Direct protein sequencing; Disulfide bond; Myotoxin;
KW Secreted; Signal; Toxin.
FT SIGNAL 1..16
FT /evidence="ECO:0000269|PubMed:28265084"
FT CHAIN 17..138
FT /note="Basic phospholipase A2 homolog MjTX-I"
FT /evidence="ECO:0000269|PubMed:10620318"
FT /id="PRO_0000161623"
FT BINDING 34
FT /ligand="suramin"
FT /ligand_id="ChEBI:CHEBI:180911"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000269|PubMed:29985425"
FT BINDING 43
FT /ligand="varespladib"
FT /ligand_id="ChEBI:CHEBI:189666"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000269|PubMed:33865953"
FT BINDING 45
FT /ligand="suramin"
FT /ligand_id="ChEBI:CHEBI:180911"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000269|PubMed:29985425"
FT BINDING 48
FT /ligand="suramin"
FT /ligand_id="ChEBI:CHEBI:180911"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000269|PubMed:29985425"
FT BINDING 63
FT /ligand="varespladib"
FT /ligand_id="ChEBI:CHEBI:189666"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000269|PubMed:33865953"
FT BINDING 64
FT /ligand="varespladib"
FT /ligand_id="ChEBI:CHEBI:189666"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000269|PubMed:33865953"
FT BINDING 85
FT /ligand="suramin"
FT /ligand_id="ChEBI:CHEBI:180911"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000269|PubMed:29985425"
FT SITE 49
FT /note="Membrane-docking site (MDoS)"
FT /evidence="ECO:0000305|PubMed:33865953"
FT SITE 64
FT /note="Membrane-docking site (MDoS)"
FT /evidence="ECO:0000305|PubMed:33865953"
FT SITE 68
FT /note="Membrane-docking site (MDoS)"
FT /evidence="ECO:0000305|PubMed:33865953"
FT SITE 76
FT /note="Membrane-docking site (MDoS)"
FT /evidence="ECO:0000305|PubMed:33865953"
FT SITE 77
FT /note="Membrane-docking site (MDoS)"
FT /evidence="ECO:0000305|PubMed:33865953"
FT SITE 128
FT /note="Membrane-disrupting site (MDiS)"
FT /evidence="ECO:0000305|PubMed:33865953"
FT SITE 129
FT /note="Membrane-docking site (MDoS)"
FT /evidence="ECO:0000305|PubMed:33865953"
FT SITE 131
FT /note="Membrane-disrupting site (MDiS)"
FT /evidence="ECO:0000305|PubMed:33865953"
FT SITE 134
FT /note="Membrane-docking site (MDoS)"
FT /evidence="ECO:0000305|PubMed:33865953"
FT DISULFID 42..132
FT /evidence="ECO:0000269|PubMed:23573271,
FT ECO:0000269|PubMed:29985425, ECO:0000269|PubMed:33865953,
FT ECO:0007744|PDB:3T0R, ECO:0007744|PDB:6CE2,
FT ECO:0007744|PDB:7LYE"
FT DISULFID 44..60
FT /evidence="ECO:0000269|PubMed:23573271,
FT ECO:0000269|PubMed:29985425, ECO:0000269|PubMed:33865953,
FT ECO:0007744|PDB:3T0R, ECO:0007744|PDB:6CE2,
FT ECO:0007744|PDB:7LYE"
FT DISULFID 59..111
FT /evidence="ECO:0000269|PubMed:23573271,
FT ECO:0000269|PubMed:29985425, ECO:0000269|PubMed:33865953,
FT ECO:0007744|PDB:3T0R, ECO:0007744|PDB:6CE2,
FT ECO:0007744|PDB:7LYE"
FT DISULFID 65..138
FT /evidence="ECO:0000269|PubMed:23573271,
FT ECO:0000269|PubMed:29985425, ECO:0000269|PubMed:33865953,
FT ECO:0007744|PDB:3T0R, ECO:0007744|PDB:6CE2,
FT ECO:0007744|PDB:7LYE"
FT DISULFID 66..104
FT /evidence="ECO:0000269|PubMed:23573271,
FT ECO:0000269|PubMed:29985425, ECO:0000269|PubMed:33865953,
FT ECO:0007744|PDB:3T0R, ECO:0007744|PDB:6CE2,
FT ECO:0007744|PDB:7LYE"
FT DISULFID 73..97
FT /evidence="ECO:0000269|PubMed:23573271,
FT ECO:0000269|PubMed:29985425, ECO:0000269|PubMed:33865953,
FT ECO:0007744|PDB:3T0R, ECO:0007744|PDB:6CE2,
FT ECO:0007744|PDB:7LYE"
FT DISULFID 91..102
FT /evidence="ECO:0000269|PubMed:23573271,
FT ECO:0000269|PubMed:29985425, ECO:0000269|PubMed:33865953,
FT ECO:0007744|PDB:3T0R, ECO:0007744|PDB:6CE2,
FT ECO:0007744|PDB:7LYE"
FT CONFLICT 34
FT /note="V -> A (in Ref. 2; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 72
FT /note="D -> N (in Ref. 2; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 74
FT /note="N -> D (in Ref. 2; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 86
FT /note="D -> N (in Ref. 2; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 96
FT /note="S -> A (in Ref. 6; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 100
FT /note="E -> Q (in Ref. 2; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 123
FT /note="Missing (in Ref. 2; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 125
FT /note="N -> D (in Ref. 2; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 133
FT /note="K -> D (in Ref. 2; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 136
FT /note="D -> L (in Ref. 6; AA sequence)"
FT /evidence="ECO:0000305"
FT HELIX 2..13
FT /evidence="ECO:0007829|PDB:7LYE"
FT HELIX 17..21
FT /evidence="ECO:0007829|PDB:7LYE"
FT TURN 25..27
FT /evidence="ECO:0007829|PDB:7LYE"
FT STRAND 30..32
FT /evidence="ECO:0007829|PDB:7LYE"
FT HELIX 39..52
FT /evidence="ECO:0007829|PDB:7LYE"
FT TURN 59..61
FT /evidence="ECO:0007829|PDB:7LYE"
FT STRAND 66..68
FT /evidence="ECO:0007829|PDB:7LYE"
FT STRAND 70..75
FT /evidence="ECO:0007829|PDB:7LYE"
FT HELIX 80..98
FT /evidence="ECO:0007829|PDB:7LYE"
FT HELIX 100..102
FT /evidence="ECO:0007829|PDB:7LYE"
FT HELIX 105..107
FT /evidence="ECO:0007829|PDB:6CE2"
FT STRAND 108..111
FT /evidence="ECO:0007829|PDB:3T0R"
SQ SEQUENCE 138 AA; 15618 MW; A1947D2533064922 CRC64;
MRTLWIMAVL LVGVEGSLVE LGKMILQETG KNPVTSYGAY GCNCGVLGRG KPKDATDRCC
YVHKCCYKKL TDCNPKKDRY SYSWKDKTIV CGENNSCLKE LCECDKAVAI CLRENLDTYN
KKYKNNYLKP FCKKADPC
