CA1A_CONBU
ID CA1A_CONBU Reviewed; 60 AA.
AC P69657;
DT 29-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 29-MAR-2005, sequence version 1.
DT 03-AUG-2022, entry version 64.
DE RecName: Full=Alpha-conotoxin BuIA {ECO:0000303|PubMed:15520009, ECO:0000303|PubMed:16979596, ECO:0000303|PubMed:17445276};
DE AltName: Full=Conotoxin Bu1.3 {ECO:0000303|PubMed:20143226};
DE Flags: Precursor;
OS Conus bullatus (Bubble cone).
OC Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Textilia.
OX NCBI_TaxID=89438;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], SYNTHESIS OF 44-56, AMIDATION AT CYS-56, AND
RP FUNCTION.
RC TISSUE=Venom duct;
RX PubMed=15520009; DOI=10.1074/jbc.m406281200;
RA Azam L., Dowell C., Watkins M., Stitzel J.A., Olivera B.M., McIntosh J.M.;
RT "Alpha-conotoxin BuIA, a novel peptide from Conus bullatus, distinguishes
RT among neuronal nicotinic acetylcholine receptors.";
RL J. Biol. Chem. 280:80-87(2005).
RN [2]
RP FUNCTION, AMIDATION AT CYS-56, AND SYNTHESIS OF 44-56.
RX PubMed=16964981; DOI=10.1021/bi0611715;
RA Shiembob D.L., Roberts R.L., Luetje C.W., McIntosh J.M.;
RT "Determinants of alpha-conotoxin BuIA selectivity on the nicotinic
RT acetylcholine receptor beta subunit.";
RL Biochemistry 45:11200-11207(2006).
RN [3]
RP MUTAGENESIS OF SER-47; THR-48; ALA-52; VAL-53; LEU-54 AND TYR-55, SYNTHETIC
RP HYDROXYPRO-49 AND HYDROXYPRO-50, AMIDATION AT CYS-56, SYNTHESIS OF 44-56,
RP AND SITE.
RX PubMed=20739611; DOI=10.1096/fj.10-166272;
RA Azam L., Maskos U., Changeux J.P., Dowell C.D., Christensen S.,
RA De Biasi M., McIntosh J.M.;
RT "Alpha-conotoxin BuIA[T5A;P6O]: a novel ligand that discriminates between
RT alpha6beta4 and alpha6beta2 nicotinic acetylcholine receptors and blocks
RT nicotine-stimulated norepinephrine release.";
RL FASEB J. 24:5113-5123(2010).
RN [4]
RP FUNCTION.
RX PubMed=22751014; DOI=10.1096/fj.12-204487;
RA Kim H.W., McIntosh J.M.;
RT "alpha6 nAChR subunit residues that confer alpha-conotoxin BuIA
RT selectivity.";
RL FASEB J. 26:4102-4110(2012).
RN [5]
RP DERIVATIVE TP-2212-59.
RX PubMed=24649848; DOI=10.1021/jm500183r;
RA Chang Y.P., Banerjee J., Dowell C., Wu J., Gyanda R., Houghten R.A.,
RA Toll L., McIntosh J.M., Armishaw C.J.;
RT "Discovery of a potent and selective alpha3beta4 nicotinic acetylcholine
RT receptor antagonist from an alpha-conotoxin synthetic combinatorial
RT library.";
RL J. Med. Chem. 57:3511-3521(2014).
RN [6]
RP FUNCTION.
RX PubMed=25466886; DOI=10.1096/fj.14-262733;
RA Heghinian M.D., Mejia M., Adams D.J., Godenschwege T.A., Mari F.;
RT "Inhibition of cholinergic pathways in Drosophila melanogaster by alpha-
RT conotoxins.";
RL FASEB J. 29:1011-1018(2015).
RN [7]
RP MUTAGENESIS OF THR-48, SYNTHETIC HYDROXYPRO-49, AND SYNTHESIS OF 22-37.
RX PubMed=26330550; DOI=10.1124/mol.115.100982;
RA Hone A.J., McIntosh J.M., Azam L., Lindstrom J., Lucero L., Whiteaker P.,
RA Passas J., Blazquez J., Albillos A.;
RT "Alpha-conotoxins identify the alpha3beta4* subtype as the predominant
RT nicotinic acetylcholine receptor expressed in human adrenal chromaffin
RT cells.";
RL Mol. Pharmacol. 88:881-893(2015).
RN [8]
RP ERRATUM OF PUBMED:26330550.
RX PubMed=26783122; DOI=10.1124/mol.115.100982err;
RA Hone A.J., McIntosh J.M., Azam L., Lindstrom J., Lucero L., Whiteaker P.,
RA Passas J., Blazquez J., Albillos A.;
RT "Correction to 'alpha-conotoxins identify the alpha3beta4* subtype as the
RT predominant nicotinic acetylcholine receptor expressed in human adrenal
RT chromaffin cells'.";
RL Mol. Pharmacol. 89:322-322(2016).
RN [9]
RP STRUCTURE BY NMR OF 44-56, SYNTHESIS OF 44-56, AMIDATION AT CYS-56, AND
RP DISULFIDE BONDS.
RX PubMed=16979596; DOI=10.1016/j.bbrc.2006.08.164;
RA Chi S.-W., Kim D.-H., Olivera B.M., McIntosh J.M., Han K.-H.;
RT "NMR structure determination of alpha-conotoxin BuIA, a novel neuronal
RT nicotinic acetylcholine receptor antagonist with an unusual 4/4 disulfide
RT scaffold.";
RL Biochem. Biophys. Res. Commun. 349:1228-1234(2006).
RN [10]
RP STRUCTURE BY NMR OF 44-56, SYNTHESIS OF 44-56, AMIDATION AT CYS-56, AND
RP DISULFIDE BONDS.
RX PubMed=17445276; DOI=10.1186/1472-6807-7-28;
RA Jin A.H., Brandstaetter H., Nevin S.T., Tan C.C., Clark R.J., Adams D.J.,
RA Alewood P.F., Craik D.J., Daly N.L.;
RT "Structure of alpha-conotoxin BuIA: influences of disulfide connectivity on
RT structural dynamics.";
RL BMC Struct. Biol. 7:28-28(2007).
RN [11]
RP NOMENCLATURE.
RX PubMed=20143226; DOI=10.1007/s00239-010-9321-7;
RA Puillandre N., Watkins M., Olivera B.M.;
RT "Evolution of conus peptide genes: duplication and positive selection in
RT the A-Superfamily.";
RL J. Mol. Evol. 70:190-202(2010).
CC -!- FUNCTION: Alpha-conotoxins bind to the nicotinic acetylcholine
CC receptors (nAChR) and inhibit them. This peptide potently blocks
CC numerous mammalian nAChR subtypes: alpha-6/alpha-3-beta-2
CC (CHRNA6/CHRNA3-CHRNB2) (IC(50)=0.258 nM) > alpha-6/alpha-3-beta-4
CC (CHRNA6/CHRNA3-CHRNB4) (IC(50)=1.54 nM) > alpha-3-beta-2 (CHRNA3-
CC CHRNB2) (IC(50)=5.72 nM) > alpha-3-beta-4 (CHRNA3-CHRNB4)(IC(50)=27.7
CC nM) > alpha-4-beta-4 (CHRNA4-CHRNB4) (IC(50)=69.9 nM) > alpha-2-beta-4
CC (CHRNA2-CHRNB4) (IC(50)=121 nM) > alpha-7 (CHRNA7) (IC(50)=272 nM) >
CC alpha-2-beta-2 (CHRNA2-CHRNB2) (IC(50)=800 nM) (PubMed:15520009).
CC Recovery from toxin block is markedly slower for beta-4 versus beta-2
CC subunit-containing nAChRs (PubMed:15520009, PubMed:16964981). Residues
CC Thr-83, Val-135 and Phe-143 in the rat beta-2 subunit and Lys-81, Ile-
CC 133 and Gln-141 in the rat beta-4 subunit are critical to off-rate
CC differences (PubMed:16964981). Thus, this toxin represents a novel
CC probe for distinguishing between beta-2 and beta-4 subunit-containing
CC nAChRs (PubMed:15520009, PubMed:16964981). Also exhibits inhibition of
CC D.melanogaster alpha-7 nAChRs (PubMed:25466886).
CC {ECO:0000269|PubMed:15520009, ECO:0000269|PubMed:16964981,
CC ECO:0000269|PubMed:17445276, ECO:0000269|PubMed:25466886}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom duct. {ECO:0000305}.
CC -!- DOMAIN: The cysteine framework is I (CC-C-C). Alpha4/4 pattern.
CC {ECO:0000305}.
CC -!- PTM: The native globular disulfide connectivity of this toxin displays
CC multiple conformations in solution. In contrast, the non-native ribbon
CC isomer has a well-defined conformation. This ribbon isomer is inactive
CC on alpha-3-beta-2 (CHRNA3-CHRNB2) and alpha-3-beta-4 (CHRNA3-
CC CHRNB4)nAChR. {ECO:0000269|PubMed:17445276}.
CC -!- PTM: Post-translational modification of Pro-49 into hydroxyproline
CC [P49O] induces a 2800-fold decrease in inhibition of alpha-6/alpha-3-
CC beta-2-beta-3 (CHRNA6/CHRNA3-CHRNB2-CHRNB3) and 6-fold decrease in
CC inhibition of alpha-6/alpha-3-beta-4 (CHRNA6/CHRNA3-CHRNB4).
CC {ECO:0000269|PubMed:20739611}.
CC -!- PTM: Post-translational modification of Pro-49 into hydroxyproline
CC [P49O] associated with the mutation [T48A] induces a preferential
CC inhibition of beta-4 subunit-containing nAChRs (over beta-2). On
CC mouse/rat subunits, this mutant induces potent blocks of alpha-6/alpha-
CC 3-beta-4 (CHRNA6/CHRNA3-CHRNB4), moderate block of alpha-3-beta-4
CC (CHRNA3-CHRNB4), weak block of alpha-2-beta-4 (CHRNA2-CHRNB4) nAChRs
CC and no activity on alpha-2-beta-2 (CHRNA2-CHRNB2), alpha-3-beta-2
CC (CHRNA3-CHRNB2), alpha-4-beta-2 (CHRNA4-CHRNB2), alpha-4-beta-4
CC (CHRNA4-CHRNB4), alpha-6/alpha-3-beta-2-beta-3 (CHRNA6/CHRNA3-CHRNB2-
CC CHRNB3), alpha-7 (CHRNA7) and alpha-9-alpha-10 (CHRNA9-CHRNA10) and
CC alpha-1-beta-1-delta-epsilon (CHRNA1-CHRNB1-CHRND-CHRNE) nAChRs
CC (PubMed:20739611). On human subunits, this mutant induces inhibitions
CC on alpha-6/alpha-3-beta-4 (CHRNA6/CHRNA3-CHRNB4) (IC(50)=7.4 nM), beta-
CC 4-alpha-3-beta-4-alpha-3-alpha-5 (CHRNB4-CHRNA3-CHRNB4-CHRNA3-CHRNA5)
CC (IC(50)=147 nM) and alpha-3-beta-4 (CHRNA3-CHRNB4) (IC(50)166 nM), but
CC no inhibition of alpha-3-beta-2 (CHRNA3-CHRNB2), alpha-4-beta-2
CC (CHRNA4-CHRNB2), alpha-4-beta-4 (CHRNA4-CHRNB4), alpha-6/alpha-3-beta-
CC 2-beta-3 (CHRNA6/CHRNA3-CHRNB2-CHRNB3), beta-3-alpha-6-beta-2-alpha-4-
CC beta-2 (CHRNB3-CHRNA6-CHRNB2-CHRNA4-CHRNB2) nAChRs (PubMed:26330550).
CC {ECO:0000269|PubMed:20739611, ECO:0000269|PubMed:26330550}.
CC -!- PTM: Post-translational modification of Pro-50 into hydroxyproline
CC [P50O] induces a 9-fold decrease in inhibition of alpha-6/alpha-3-beta-
CC 2-beta-3 (CHRNA6/CHRNA3-CHRNB2-CHRNB3) and a 4-fold decrease in
CC inhibition of alpha-6/alpha-3-beta-4 (CHRNA6/CHRNA3-CHRNB4).
CC {ECO:0000269|PubMed:20739611}.
CC -!- MISCELLANEOUS: Does not inhibit alpha-4-beta-2 (CHRNA4-CHRNB2) nAChR
CC (IC(50)=10.400 uM or >20 uM). {ECO:0000269|PubMed:15520009,
CC ECO:0000269|PubMed:22751014}.
CC -!- MISCELLANEOUS: Exists in two forms, due to cis-trans isomerization at
CC 49-Pro-Pro-50. {ECO:0000269|PubMed:17445276}.
CC -!- MISCELLANEOUS: The synthetic peptide TP-2212-59, with the sequence
CC GCCSHPBCFBZYC (B=Aminobutyric acid and Z=Norvaline), shows a high
CC selectivity on alpha-3-beta-4/CHRNA3-CHRNB4 (IC(50)=2.3 nM on alpha-3-
CC beta-4/CHRNA3-CHRNB4 and no inhibition on other receptors tested).
CC {ECO:0000269|PubMed:24649848}.
CC -!- SIMILARITY: Belongs to the conotoxin A superfamily. {ECO:0000305}.
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DR PDB; 2I28; NMR; -; A=44-56.
DR PDB; 2NS3; NMR; -; A=44-56.
DR PDB; 4EZ1; X-ray; 2.49 A; K/L/M/N/O=44-56.
DR PDBsum; 2I28; -.
DR PDBsum; 2NS3; -.
DR PDBsum; 4EZ1; -.
DR AlphaFoldDB; P69657; -.
DR SMR; P69657; -.
DR TCDB; 8.B.32.1.13; the nicotinic acetylcholine receptor-targeting alpha-conotoxin (a-conotoxin) family.
DR ConoServer; 409; BuIA precursor.
DR EvolutionaryTrace; P69657; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0035792; C:host cell postsynaptic membrane; IEA:UniProtKB-KW.
DR GO; GO:0030550; F:acetylcholine receptor inhibitor activity; IEA:UniProtKB-KW.
DR GO; GO:0099106; F:ion channel regulator activity; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR InterPro; IPR009958; Conotoxin_a-typ.
DR InterPro; IPR018072; Conotoxin_a-typ_CS.
DR Pfam; PF07365; Toxin_8; 1.
DR PROSITE; PS60014; ALPHA_CONOTOXIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylcholine receptor inhibiting toxin; Amidation;
KW Disulfide bond; Ion channel impairing toxin; Neurotoxin;
KW Postsynaptic neurotoxin; Secreted; Signal; Toxin.
FT SIGNAL 1..16
FT /evidence="ECO:0000255"
FT PROPEP 17..43
FT /evidence="ECO:0000250"
FT /id="PRO_0000034869"
FT PEPTIDE 44..56
FT /note="Alpha-conotoxin BuIA"
FT /evidence="ECO:0000305|PubMed:15520009,
FT ECO:0000305|PubMed:16964981, ECO:0000305|PubMed:16979596,
FT ECO:0000305|PubMed:17445276, ECO:0000305|PubMed:20739611"
FT /id="PRO_0000034870"
FT SITE 49
FT /note="Critical residue for distinguishing between alpha-6-
FT beta-2/CHRNA6-CHRNB2 and alpha-6-beta-4/CHRNA6-CHRNB4 nAChR
FT subunits"
FT /evidence="ECO:0000269|PubMed:20739611"
FT MOD_RES 56
FT /note="Cysteine amide"
FT /evidence="ECO:0000305|PubMed:15520009,
FT ECO:0000305|PubMed:16964981, ECO:0000305|PubMed:16979596,
FT ECO:0000305|PubMed:17445276, ECO:0000305|PubMed:20739611"
FT DISULFID 45..51
FT /evidence="ECO:0000269|PubMed:16979596,
FT ECO:0000269|PubMed:17445276, ECO:0007744|PDB:2I28,
FT ECO:0007744|PDB:2NS3"
FT DISULFID 46..56
FT /evidence="ECO:0000269|PubMed:16979596,
FT ECO:0000269|PubMed:17445276, ECO:0007744|PDB:2I28,
FT ECO:0007744|PDB:2NS3"
FT MUTAGEN 47
FT /note="S->A: No change in inhibition of alpha-6/alpha-3-
FT beta-2-beta-3 (CHRNA6/CHRNA3-CHRNB2-CHRNB3) nAChR. 4-fold
FT decrease in inhibition of alpha-6/alpha-3-beta-4
FT (CHRNA6/CHRNA3-CHRNB4) nAChR."
FT /evidence="ECO:0000269|PubMed:20739611"
FT MUTAGEN 48
FT /note="T->A: 16-fold decrease in inhibition of alpha-
FT 6/alpha-3-beta-2-beta-3 (CHRNA6/CHRNA3-CHRNB2-CHRNB3)
FT nAChR, 2-fold decrease in inhibition of alpha-6/alpha-3-
FT beta-4 (CHRNA6/CHRNA3-CHRNB4) nAChR. Preferential
FT inhibition of beta-4 subunit-containing nAChRs (over beta-
FT 2), potent block of alpha-6/alpha-3-beta-4 (CHRNA6/CHRNA3-
FT CHRNB4), moderate block of alpha-3-beta-4 (CHRNA3-
FT CHRNB4)and weak block of alpha-2-beta-4 (CHRNA2-CHRNB4)
FT nAChRs and no activity on alpha-2-beta-2 (CHRNA2-CHRNB2),
FT alpha-3-beta-2 (CHRNA3-CHRNB2), alpha-4-beta-2 (CHRNA4-
FT CHRNB2), alpha-4-beta-4 (CHRNA4-CHRNB4), alpha-6/alpha-3-
FT beta-2-beta-3 (CHRNA6/CHRNA3-CHRNB2-CHRNB3), alpha-7
FT (CHRNA7) and alpha-9-alpha-10 (CHRNA9-CHRNA10) and alpha-1-
FT beta-1-delta-epsilon (CHRNA1-CHRNB1-CHRND-CHRNE) nAChRs;
FT when associated with hydroxyPro-49 (see miscellaneous)."
FT /evidence="ECO:0000269|PubMed:20739611"
FT MUTAGEN 52
FT /note="A->S: 4-fold decrease in inhibition of alpha-
FT 6/alpha-3-beta-2-beta-3 (CHRNA6/CHRNA3-CHRNB2-CHRNB3)
FT nAChR. 11-fold decrease in inhibition of alpha-6/alpha-3-
FT beta-4 (CHRNA6/CHRNA3-CHRNB4) nAChR."
FT /evidence="ECO:0000269|PubMed:20739611"
FT MUTAGEN 53
FT /note="V->A: 37-fold decrease in inhibition of alpha-
FT 6/alpha-3-beta-2-beta-3 (CHRNA6/CHRNA3-CHRNB2-CHRNB3)
FT nAChR. 2-fold decrease in inhibition of alpha-6/alpha-3-
FT beta-4 (CHRNA6/CHRNA3-CHRNB4) nAChR."
FT /evidence="ECO:0000269|PubMed:20739611"
FT MUTAGEN 54
FT /note="L->A: 50-fold decrease in inhibition of alpha-
FT 6/alpha-3-beta-2-beta-3 (CHRNA6/CHRNA3-CHRNB2-CHRNB3)
FT nAChR. 6-fold decrease in inhibition of alpha-6/alpha-3-
FT beta-4 (CHRNA6/CHRNA3-CHRNB4) nAChR."
FT /evidence="ECO:0000269|PubMed:20739611"
FT MUTAGEN 55
FT /note="Y->A: 150-fold decrease in inhibition of alpha-
FT 6/alpha-3-beta-2-beta-3 (CHRNA6/CHRNA3-CHRNB2-CHRNB3)
FT nAChR. 21-fold decrease in inhibition of alpha-6/alpha-3-
FT beta-4 (CHRNA6/CHRNA3-CHRNB4) nAChR."
FT /evidence="ECO:0000269|PubMed:20739611"
FT STRAND 46..48
FT /evidence="ECO:0007829|PDB:2I28"
FT HELIX 49..55
FT /evidence="ECO:0007829|PDB:4EZ1"
SQ SEQUENCE 60 AA; 6394 MW; 86FF88338E0FCCE6 CRC64;
MFTVFLLVVL TTTVVSFPSD RASDGRNAAA NDKASDVVTL VLKGCCSTPP CAVLYCGRRR
