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CA1A_CONPR
ID   CA1A_CONPR              Reviewed;          38 AA.
AC   Q1L777;
DT   25-JUL-2006, integrated into UniProtKB/Swiss-Prot.
DT   30-MAY-2006, sequence version 1.
DT   25-MAY-2022, entry version 56.
DE   RecName: Full=Alpha-conotoxin PeIA {ECO:0000303|PubMed:15983035, ECO:0000303|PubMed:21252227, ECO:0000303|PubMed:23846688};
DE   Flags: Precursor; Fragment;
OS   Conus pergrandis (Grand cone).
OC   Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC   Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Embrikena.
OX   NCBI_TaxID=330676;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, SYNTHESIS OF 22-37, AND
RP   AMIDATION AT CYS-37.
RC   TISSUE=Hepatopancreas;
RX   PubMed=15983035; DOI=10.1074/jbc.m504102200;
RA   McIntosh J.M., Plazas P.V., Watkins M., Gomez-Casati M.E., Olivera B.M.,
RA   Elgoyhen A.B.;
RT   "A novel alpha-conotoxin, PeIA, cloned from Conus pergrandis, discriminates
RT   between rat alpha9alpha10 and alpha7 nicotinic cholinergic receptors.";
RL   J. Biol. Chem. 280:30107-30112(2005).
RN   [2]
RP   FUNCTION, STRUCTURE BY NMR, DISULFIDE BOND, AND SYNTHESIS OF 22-37.
RX   PubMed=21252227; DOI=10.1074/jbc.m110.196170;
RA   Daly N.L., Callaghan B., Clark R.J., Nevin S.T., Adams D.J., Craik D.J.;
RT   "Structure and activity of alpha-conotoxin PeIA at nicotinic acetylcholine
RT   receptor subtypes and GABA(B) receptor-coupled N-type calcium channels.";
RL   J. Biol. Chem. 286:10233-10237(2011).
RN   [3]
RP   FUNCTION, MUTAGENESIS OF SER-30; VAL-31 AND GLU-35, AND SYNTHESIS OF 22-37.
RX   PubMed=22914547; DOI=10.1124/mol.112.080853;
RA   Hone A.J., Scadden M., Gajewiak J., Christensen S., Lindstrom J.,
RA   McIntosh J.M.;
RT   "alpha-Conotoxin PeIA[S9H,V10A,E14N] potently and selectively blocks
RT   alpha6beta2beta3 versus alpha6beta4 nicotinic acetylcholine receptors.";
RL   Mol. Pharmacol. 82:972-982(2012).
RN   [4]
RP   FUNCTION, MUTAGENESIS OF SER-25; HIS-26; PRO-27; ALA-28; SER-30; VAL-31;
RP   ASN-32; HIS-33; PRO-34; GLU-35 AND LEU-36, AND SYNTHESIS OF 22-37.
RX   PubMed=23846688; DOI=10.1074/jbc.m113.482059;
RA   Hone A.J., Ruiz M., Scadden M., Christensen S., Gajewiak J., Azam L.,
RA   McIntosh J.M.;
RT   "Positional scanning mutagenesis of alpha-conotoxin PeIA identifies
RT   critical residues that confer potency and selectivity for
RT   alpha6/alpha3beta2beta3 and alpha3beta2 nicotinic acetylcholine
RT   receptors.";
RL   J. Biol. Chem. 288:25428-25439(2013).
RN   [5]
RP   MUTAGENESIS OF ALA-28; SER-30; VAL-31; ASN-32 AND GLU-35, AND SYNTHESIS OF
RP   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   [6]
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   [7]
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   [8]
RP   FUNCTION, AND MUTAGENESIS OF CYS-37.
RX   PubMed=32101438; DOI=10.1021/acs.jmedchem.9b01536;
RA   Liang J., Tae H.S., Xu X., Jiang T., Adams D.J., Yu R.;
RT   "Dimerization of alpha-conotoxins as a strategy to enhance the inhibition
RT   of the human alpha7 and alpha9alpha10 nicotinic acetylcholine Receptors.";
RL   J. Med. Chem. 63:2974-2985(2020).
RN   [9]
RP   FUNCTION, SYNTHESIS OF 22-37, AND MUTAGENESIS OF ALA-28; SER-30; ASN-32 AND
RP   LEU-36.
RX   PubMed=33523678; DOI=10.1021/acs.jmedchem.0c01973;
RA   Hone A.J., Kaas Q., Kearns I., Hararah F., Gajewiak J., Christensen S.,
RA   Craik D.J., McIntosh J.M.;
RT   "Computational and functional mapping of human and rat alpha6beta4
RT   nicotinic acetylcholine receptors reveals species-specific ligand-binding
RT   motifs.";
RL   J. Med. Chem. 64:1685-1700(2021).
CC   -!- FUNCTION: Alpha-conotoxins act on postsynaptic membranes, they bind to
CC       the nicotinic acetylcholine receptors (nAChR) and thus inhibit them.
CC       This synthetic peptide potently and reversibly blocks alpha-9-alpha-
CC       10/CHRNA9-CHRNA10 nAChR (IC(50)=6.9-54.9 nM), alpha-3-beta-2/CHRNA3-
CC       CHRNB2 (IC(50)=9.7-97.5 nM) and alpha-6/alpha-3-beta-2-beta-3
CC       (CHRNA6/CHRNA3-CHRNB2-CHRNB3) (IC(50)=11.1-17.2 nM) (PubMed:15983035,
CC       PubMed:21252227, PubMed:22914547, PubMed:23846688, PubMed:32101438). It
CC       also inhibits alpha-6/alpha-3-beta-4 (CHRNA6/CHRNA3-CHRNB4) nAChR with
CC       a higher potency on human (IC(50)=6.75 nM) than on rat receptors
CC       (IC(50)=130-147 nM) (PubMed:22914547, PubMed:33523678). Also shows a
CC       weak ability to inhibit alpha-3-beta-4/CHRNA3-CHRNB4 (IC(50)=480-1500
CC       nM) (PubMed:15983035, PubMed:22914547). This synthetic toxin also
CC       inhibits N-type calcium channels (Ca2.2/CACNA1B) (IC(50)=1.1 nM) via
CC       the activation of the G protein-coupled GABA(B) receptor in DRG neurons
CC       (PubMed:21252227). Also exhibits inhibition of D.melanogaster alpha-7
CC       nAChRs (PubMed:25466886). {ECO:0000269|PubMed:15983035,
CC       ECO:0000269|PubMed:21252227, ECO:0000269|PubMed:22914547,
CC       ECO:0000269|PubMed:23846688, ECO:0000269|PubMed:25466886,
CC       ECO:0000269|PubMed:33523678}.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:P85013}.
CC   -!- TISSUE SPECIFICITY: Expressed by the venom duct. {ECO:0000305}.
CC   -!- DOMAIN: The cysteine framework is I (CC-C-C). Alpha4/7 pattern.
CC       {ECO:0000305}.
CC   -!- PTM: The hydroxylation at position Pro-27 is critical, since an
CC       hydroxylation at this position decreases potency of the toxin to
CC       inhibit both alpha-3-beta-2 (1300-fold) and alpha-6/alpha-3-beta-2-
CC       beta-3 (130-fold) nAChRs. {ECO:0000269|PubMed:23846688}.
CC   -!- PTM: A non-modified residue at position Pro-34 is critical, since a
CC       hydroxylation at this position decreases potency of the toxin to
CC       inhibit alpha-3-beta-2 (1-45-fold) and increases potency to inhibit
CC       alpha-6/alpha-3-beta-2-beta-3 (1.77-fold) nAChRs.
CC       {ECO:0000269|PubMed:23846688}.
CC   -!- MISCELLANEOUS: This toxin shows a very weak or no inhibition on
CC       mammalian muscle alpha-1-beta-1-gamma-delta, neuronal alpha-7, and
CC       neuronal alpha-4-beta-2 nAChR. {ECO:0000269|PubMed:15983035,
CC       ECO:0000269|PubMed:21252227, ECO:0000269|PubMed:32101438}.
CC   -!- MISCELLANEOUS: The mutant [A28V, S30H, V31A, N32R, E35A] is >15'000-
CC       fold more potent at inhibiting alpha-6/alpha-3-beta-2-beta-3 than
CC       alpha-3-beta-2, and is essentially inactive on all other non-alpha6-
CC       containing nAChRs including alpha-3-beta-4, alpha-4-beta-2, alpha-4-
CC       beta-4 and alpha-7 (PubMed:23846688). This mutant shows inhibition on
CC       alpha-6/alpha-3-beta-2-beta-3 (IC(50)=3.8 nM), beta-3-alpha-6-beta-2-
CC       alpha-4-beta-2 (IC(50)=6.3 nM), alpha-3-beta-4 (IC(50)=3.7 uM), alpha-
CC       3-beta-2 (IC(50)=6.1 uM), beta-4-alpha-3-beta-4-alpha-3-alpha-5
CC       (IC(50)=9.2 uM), and does not inhibit alpha-4-beta-2 and alpha-4-beta-4
CC       nAChRs (PubMed:26330550). {ECO:0000269|PubMed:23846688,
CC       ECO:0000269|PubMed:26330550}.
CC   -!- MISCELLANEOUS: The mutant [S30H, V31A, E35N] is >290-fold more potent
CC       at inhibiting alpha-6/alpha-3-beta-2-beta-3 than alpha-6/alpha-3-beta-
CC       4, demonstrating that it can discriminate between alpha-6-beta-2-beta-3
CC       and alpha-6-beta-4 nAChRs. {ECO:0000269|PubMed:22914547}.
CC   -!- MISCELLANEOUS: The mutant PeIA-5667 [A28V, S30N, N11R, L36I] is much
CC       more potent at inhibiting alpha-6/alpha-3-beta-4 nAChR than the wild-
CC       type toxin on both rat (IC(50)=0.20 nM) and human channels (IC(50)=0.48
CC       nM). It shows moderate activity on alpha-3-beta-4 nAChR (IC(50)=179-230
CC       nM on rat and human channels) and on alpha-6/alpha-3-beta-2-beta-3
CC       nAChR (IC(50)=111-135 nM on rat and human channels). It does not show
CC       activity on all other channels tested. {ECO:0000269|PubMed:33523678}.
CC   -!- SIMILARITY: Belongs to the conotoxin A superfamily. {ECO:0000305}.
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DR   EMBL; DQ008450; AAY57814.1; -; Genomic_DNA.
DR   PDB; 5JME; X-ray; 2.34 A; F/G/H/I=22-37.
DR   PDBsum; 5JME; -.
DR   AlphaFoldDB; Q1L777; -.
DR   SMR; Q1L777; -.
DR   ConoServer; 5; PeIA precursor.
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:0005246; F:calcium channel regulator activity; IEA:UniProtKB-KW.
DR   GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR   InterPro; IPR009958; Conotoxin_a-typ.
DR   Pfam; PF07365; Toxin_8; 1.
PE   3: Inferred from homology;
KW   3D-structure; Acetylcholine receptor inhibiting toxin; Amidation;
KW   Calcium channel impairing toxin; Disulfide bond;
KW   Ion channel impairing toxin; Neurotoxin; Postsynaptic neurotoxin; Secreted;
KW   Toxin.
FT   PROPEP          <1..21
FT                   /evidence="ECO:0000305"
FT                   /id="PRO_0000247850"
FT   PEPTIDE         22..37
FT                   /note="Alpha-conotoxin PeIA"
FT                   /evidence="ECO:0000305|PubMed:15983035,
FT                   ECO:0000305|PubMed:21252227"
FT                   /id="PRO_0000247851"
FT   REGION          25..27
FT                   /note="Ser-Xaa-Pro motif, crucial for potent interaction
FT                   with nAChR"
FT                   /evidence="ECO:0000250|UniProtKB:P56636"
FT   SITE            26
FT                   /note="Important residue for inhibiting alpha-3-beta-2
FT                   nAChR"
FT                   /evidence="ECO:0000269|PubMed:23846688"
FT   SITE            27
FT                   /note="Important residue for inhibiting alpha-3-beta-2
FT                   nAChR"
FT                   /evidence="ECO:0000269|PubMed:23846688"
FT   SITE            30
FT                   /note="Residue that is not optimum for the most potent
FT                   inhibition of alpha-3-beta-2 and alpha-6/alpha-3-beta-2-
FT                   beta-3 and alpha-6/alpha-3-beta-4"
FT                   /evidence="ECO:0000269|PubMed:22914547,
FT                   ECO:0000269|PubMed:23846688"
FT   SITE            31
FT                   /note="Important residue for inhibiting alpha-3-beta-2
FT                   nAChR"
FT                   /evidence="ECO:0000269|PubMed:23846688"
FT   SITE            32
FT                   /note="Important residue for inhibiting alpha-3-beta-2
FT                   nAChR"
FT                   /evidence="ECO:0000269|PubMed:23846688"
FT   SITE            33
FT                   /note="Important residue for inhibiting alpha-3-beta-2 and
FT                   alpha-6/alpha-3-beta-2-beta-3 nAChR"
FT                   /evidence="ECO:0000269|PubMed:23846688"
FT   MOD_RES         37
FT                   /note="Cysteine amide"
FT                   /evidence="ECO:0000305|PubMed:15983035"
FT   DISULFID        23..29
FT                   /evidence="ECO:0000305|PubMed:21252227,
FT                   ECO:0000312|PDB:5JME"
FT   DISULFID        24..37
FT                   /evidence="ECO:0000305|PubMed:21252227,
FT                   ECO:0000312|PDB:5JME"
FT   MUTAGEN         25
FT                   /note="S->A: 1.9-fold decrease in ability to inhibit alpha-
FT                   3-beta-2 nAChR and 1.4-fold increase in ability to inhibit
FT                   alpha-6/alpha-3-beta-2-beta-3 nAChR."
FT                   /evidence="ECO:0000269|PubMed:23846688"
FT   MUTAGEN         26
FT                   /note="H->A: 1350-fold and 65-fold decrease in ability to
FT                   inhibit alpha-3-beta-2 and alpha-6/alpha-3-beta-2-beta-3
FT                   nAChR, respectively."
FT                   /evidence="ECO:0000269|PubMed:23846688"
FT   MUTAGEN         26
FT                   /note="H->N: 1.4-fold decrease in ability to inhibit alpha-
FT                   3-beta-2 nAChR and 6.4-fold increase in ability to inhibit
FT                   alpha-6/alpha-3-beta-2-beta-3 nAChR."
FT                   /evidence="ECO:0000269|PubMed:23846688"
FT   MUTAGEN         27
FT                   /note="P->A: 580-fold and 20-fold decrease in ability to
FT                   inhibit alpha-3-beta-2 and alpha-6/alpha-3-beta-2-beta-3
FT                   nAChR, respectively."
FT                   /evidence="ECO:0000269|PubMed:23846688"
FT   MUTAGEN         28
FT                   /note="A->V: 4.5-fold decrease in ability to inhibit alpha-
FT                   3-beta-2 nAChR and 2.5-fold increase in ability to inhibit
FT                   alpha-6/alpha-3-beta-2-beta-3 nAChR. In PeIA-5667; 33- and
FT                   270-fold increase in ability to inhibit rat and human
FT                   alpha-6-beta-4 nAChRs, respectively (IC(50)=0.20-0.48 nM)."
FT                   /evidence="ECO:0000269|PubMed:23846688,
FT                   ECO:0000269|PubMed:33523678"
FT   MUTAGEN         30
FT                   /note="S->A: 3.3-fold and 2.4-fold increase in ability to
FT                   inhibit alpha-3-beta-2 and alpha-6/alpha-3-beta-2-beta-3
FT                   nAChR, respectively."
FT                   /evidence="ECO:0000269|PubMed:23846688"
FT   MUTAGEN         30
FT                   /note="S->H: 14-fold, 11-fold and 10-fold increase in
FT                   ability to inhibit alpha-3-beta-2, alpha-6/alpha-3-beta-2-
FT                   beta-3 and alpha-6/alpha-3-beta-4 nAChR, respectively."
FT                   /evidence="ECO:0000269|PubMed:22914547"
FT   MUTAGEN         30
FT                   /note="S->N: In PeIA-5667; 33- and 270-fold increase in
FT                   ability to inhibit rat and human alpha-6-beta-4 nAChRs,
FT                   respectively (IC(50)=0.20-0.48 nM)."
FT                   /evidence="ECO:0000269|PubMed:33523678"
FT   MUTAGEN         30
FT                   /note="S->R: 4.6-fold and 7.5-fold increase in ability to
FT                   inhibit alpha-3-beta-2 and alpha-6/alpha-3-beta-2-beta-3
FT                   nAChR, respectively."
FT                   /evidence="ECO:0000269|PubMed:23846688"
FT   MUTAGEN         31
FT                   /note="V->A: 4.4-fold and 4.6-fold increase in ability to
FT                   inhibit alpha-3-beta-2 and alpha-6/alpha-3-beta-2-beta-3
FT                   nAChR, respectively, and 2-fold decrease in ability to
FT                   inhibit alpha-6/alpha-3-beta-4."
FT                   /evidence="ECO:0000269|PubMed:22914547"
FT   MUTAGEN         31
FT                   /note="V->L: 5-fold increase in ability to inhibit alpha-3-
FT                   beta-2 nAChR and 1.1-fold decrease in ability to inhibit
FT                   alpha-6/alpha-3-beta-2-beta-3 nAChR."
FT                   /evidence="ECO:0000269|PubMed:23846688"
FT   MUTAGEN         31
FT                   /note="V->R: 2400-fold and 33-fold decrease in ability to
FT                   inhibit alpha-3-beta-2 and alpha-6/alpha-3-beta-2-beta-3
FT                   nAChR, respectively."
FT                   /evidence="ECO:0000269|PubMed:23846688"
FT   MUTAGEN         32
FT                   /note="N->A: 2.4-fold and 1.7-fold decrease in ability to
FT                   inhibit alpha-3-beta-2 and alpha-6/alpha-3-beta-2-beta-3
FT                   nAChR, respectively."
FT                   /evidence="ECO:0000269|PubMed:23846688"
FT   MUTAGEN         32
FT                   /note="N->E: 2.0-fold and 6.6-fold decrease in ability to
FT                   inhibit alpha-3-beta-2 and alpha-6/alpha-3-beta-2-beta-3
FT                   nAChR, respectively."
FT                   /evidence="ECO:0000269|PubMed:23846688"
FT   MUTAGEN         32
FT                   /note="N->K: 2400-fold and 2.4-fold decrease in ability to
FT                   inhibit alpha-3-beta-2 and alpha-6/alpha-3-beta-2-beta-3
FT                   nAChR, respectively."
FT                   /evidence="ECO:0000269|PubMed:23846688"
FT   MUTAGEN         32
FT                   /note="N->R: 1600-fold and 2.7-fold decrease in ability to
FT                   inhibit alpha-3-beta-2 and alpha-6/alpha-3-beta-2-beta-3
FT                   nAChR, respectively. In PeIA-5667; 33- and 270-fold
FT                   increase in ability to inhibit rat and human alpha-6-beta-4
FT                   nAChRs, respectively (IC(50)=0.20-0.48 nM)."
FT                   /evidence="ECO:0000269|PubMed:23846688,
FT                   ECO:0000269|PubMed:33523678"
FT   MUTAGEN         33
FT                   /note="H->A: 2700-fold and 420-fold decrease in ability to
FT                   inhibit alpha-3-beta-2 and alpha-6/alpha-3-beta-2-beta-3
FT                   nAChR, respectively."
FT                   /evidence="ECO:0000269|PubMed:23846688"
FT   MUTAGEN         34
FT                   /note="P->A: 3.3-fold decrease in ability to inhibit alpha-
FT                   3-beta-2 nAChR and 1.3-fold increase in ability to inhibit
FT                   alpha-6/alpha-3-beta-2-beta-3 nAChR."
FT                   /evidence="ECO:0000269|PubMed:23846688"
FT   MUTAGEN         34
FT                   /note="P->S: 1.5-fold decrease in ability to inhibit alpha-
FT                   3-beta-2 and no change in inhibition of alpha-6/alpha-3-
FT                   beta-2-beta-3 nAChR, respectively."
FT                   /evidence="ECO:0000269|PubMed:23846688"
FT   MUTAGEN         35
FT                   /note="E->A: 5.2-fold decrease in ability to inhibit alpha-
FT                   3-beta-2 nAChR and 1.4-fold increase in ability to inhibit
FT                   alpha-6/alpha-3-beta-2-beta-3 nAChR."
FT                   /evidence="ECO:0000269|PubMed:23846688"
FT   MUTAGEN         35
FT                   /note="E->N: 15-fold, 2-fold and 3-fold decrease in ability
FT                   to inhibit alpha-3-beta-2, alpha-6/alpha-3-beta-2-beta-3
FT                   and alpha-6/alpha-3-beta-4 nAChR, respectively."
FT                   /evidence="ECO:0000269|PubMed:22914547"
FT   MUTAGEN         36
FT                   /note="L->A: 7.2-fold and 4.8-fold decrease in ability to
FT                   inhibit alpha-3-beta-2 and alpha-6/alpha-3-beta-2-beta-3
FT                   nAChR, respectively."
FT                   /evidence="ECO:0000269|PubMed:23846688"
FT   MUTAGEN         36
FT                   /note="L->I: In PeIA-5667; 33- and 270-fold increase in
FT                   ability to inhibit rat and human alpha-6-beta-4 nAChRs,
FT                   respectively (IC(50)=0.20-0.48 nM)."
FT                   /evidence="ECO:0000269|PubMed:33523678"
FT   MUTAGEN         37
FT                   /note="C->CGRRRRGGCCSHPACSVNHPELC: PeIA dimer; Increase in
FT                   activity on both alpha-9-alpha-10/CHRNA9-CHRNA10 and alpha-
FT                   7/CHRNA7 nAChRs."
FT                   /evidence="ECO:0000269|PubMed:32101438"
FT   NON_TER         1
FT   HELIX           23..25
FT                   /evidence="ECO:0007829|PDB:5JME"
FT   HELIX           27..30
FT                   /evidence="ECO:0007829|PDB:5JME"
FT   TURN            34..36
FT                   /evidence="ECO:0007829|PDB:5JME"
SQ   SEQUENCE   38 AA;  3900 MW;  AE40EFB659EB0EFC CRC64;
     FDGRNAAAND KASDLVALTV RGCCSHPACS VNHPELCG
 
 
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