CA1A_CONPE
ID CA1A_CONPE Reviewed; 16 AA.
AC P50984;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1996, sequence version 1.
DT 25-MAY-2022, entry version 98.
DE RecName: Full=Alpha-conotoxin PnIA {ECO:0000303|PubMed:8068627, ECO:0000303|PubMed:8740364};
DE Short=Alpha-PnIA {ECO:0000303|PubMed:8068627, ECO:0000303|PubMed:8740364};
OS Conus pennaceus (Feathered cone) (Conus episcopus).
OC Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Darioconus.
OX NCBI_TaxID=37335;
RN [1]
RP PROTEIN SEQUENCE, AMIDATION AT CYS-16, FUNCTION, AND SUBCELLULAR LOCATION.
RC TISSUE=Venom;
RX PubMed=8068627; DOI=10.1021/bi00198a018;
RA Fainzilber M., Hasson A., Oren R., Burlingame A.L., Gordon D., Spira M.E.,
RA Zlotkin E.;
RT "New mollusc-specific alpha-conotoxins block Aplysia neuronal acetylcholine
RT receptors.";
RL Biochemistry 33:9523-9529(1994).
RN [2]
RP SULFATION AT TYR-15.
RX PubMed=10226369;
RX DOI=10.1002/(sici)1096-9888(199904)34:4<447::aid-jms801>3.0.co;2-1;
RA Wolfender J.L., Chu F., Ball H., Wolfender F., Fainzilber M., Baldwin M.A.,
RA Burlingame A.L.;
RT "Identification of tyrosine sulfation in Conus pennaceus conotoxins alpha-
RT PnIA and alpha-PnIB: further investigation of labile sulfo- and
RT phosphopeptides by electrospray, matrix-assisted laser
RT desorption/ionization (MALDI) and atmospheric pressure MALDI mass
RT spectrometry.";
RL J. Mass Spectrom. 34:447-454(1999).
RN [3]
RP FUNCTION, SYNTHESIS, AND MUTAGENESIS OF ALA-10 AND ASN-11.
RX PubMed=10545176; DOI=10.1021/bi991252j;
RA Luo S., Nguyen T.A., Cartier G.E., Olivera B.M., Yoshikami D.,
RA McIntosh J.M.;
RT "Single-residue alteration in alpha-conotoxin PnIA switches its nAChR
RT subtype selectivity.";
RL Biochemistry 38:14542-14548(1999).
RN [4]
RP FUNCTION, AND 3D-STRUCTURE MODELING.
RX PubMed=12734390; DOI=10.1124/jpet.103.051656;
RA Everhart D., Reiller E., Mirzoian A., McIntosh J.M., Malhotra A.,
RA Luetje C.W.;
RT "Identification of residues that confer alpha-conotoxin-PnIA sensitivity on
RT the alpha 3 subunit of neuronal nicotinic acetylcholine receptors.";
RL J. Pharmacol. Exp. Ther. 306:664-670(2003).
RN [5]
RP FUNCTION ON ALPHA-3-BETA-2 AND ALPHA-4-BETA-2 NACHR, AND MUTAGENESIS OF
RP ALA-10.
RX PubMed=15929983; DOI=10.1074/jbc.m504229200;
RA Dutertre S., Nicke A., Lewis R.J.;
RT "Beta2 subunit contribution to 4/7 alpha-conotoxin binding to the nicotinic
RT acetylcholine receptor.";
RL J. Biol. Chem. 280:30460-30468(2005).
RN [6]
RP FUNCTION, AND MUTAGENESIS OF LEU-5 AND ALA-10.
RX PubMed=17660751; DOI=10.1038/sj.emboj.7601785;
RA Dutertre S., Ulens C., Buettner R., Fish A., van Elk R., Kendel Y.,
RA Hopping G., Alewood P.F., Schroeder C., Nicke A., Smit A.B., Sixma T.K.,
RA Lewis R.J.;
RT "AChBP-targeted alpha-conotoxin correlates distinct binding orientations
RT with nAChR subtype selectivity.";
RL EMBO J. 26:3858-3867(2007).
RN [7]
RP FUNCTION ON ALPHA-7 AND ALPHA-3-BETA-4, SYNTHESIS, AND MUTAGENESIS OF
RP ALA-10.
RX PubMed=19131337; DOI=10.1074/jbc.m806136200;
RA Armishaw C., Jensen A.A., Balle T., Clark R.J., Harpsoee K., Skonberg C.,
RA Liljefors T., Stroemgaard K.;
RT "Rational design of alpha-conotoxin analogues targeting alpha7 nicotinic
RT acetylcholine receptors: improved antagonistic activity by incorporation of
RT proline derivatives.";
RL J. Biol. Chem. 284:9498-9512(2009).
RN [8]
RP FUNCTION.
RX PubMed=22024738; DOI=10.1096/fj.11-195883;
RA Hone A.J., Meyer E.L., McIntyre M., McIntosh J.M.;
RT "Nicotinic acetylcholine receptors in dorsal root ganglion neurons include
RT the alpha6beta4* subtype.";
RL FASEB J. 26:917-926(2012).
RN [9]
RP MUTAGENESIS OF ALA-10, AND FUNCTION.
RX PubMed=25101833; DOI=10.1016/j.bcp.2014.07.025;
RA Hopping G., Wang C.I., Hogg R.C., Nevin S.T., Lewis R.J., Adams D.J.,
RA Alewood P.F.;
RT "Hydrophobic residues at position 10 of alpha-conotoxin PnIA influence
RT subtype selectivity between alpha7 and alpha3beta2 neuronal nicotinic
RT acetylcholine receptors.";
RL Biochem. Pharmacol. 91:534-542(2014).
RN [10]
RP MUTAGENESIS OF ALA-10, AND SYNTHESIS.
RX PubMed=30025921; DOI=10.1016/j.neuropharm.2018.07.019;
RA Yu J., Zhu X., Zhang L., Kudryavtsev D., Kasheverov I., Lei Y.,
RA Zhangsun D., Tsetlin V., Luo S.;
RT "Species specificity of rat and human alpha7 nicotinic acetylcholine
RT receptors towards different classes of peptide and protein antagonists.";
RL Neuropharmacology 139:226-237(2018).
RN [11]
RP FUNCTION.
RX PubMed=32272633; DOI=10.3390/md18040193;
RA Osipov A.V., Terpinskaya T.I., Yanchanka T., Balashevich T., Zhmak M.N.,
RA Tsetlin V.I., Utkin Y.N.;
RT "Alpha-conotoxins enhance both the in vivo suppression of Ehrlich carcinoma
RT growth and in vitro reduction in cell viability elicited by cyclooxygenase
RT and lipoxygenase inhibitors.";
RL Mar. Drugs 18:1-11(2020).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS), AND DISULFIDE BONDS.
RX PubMed=8740364; DOI=10.1016/s0969-2126(96)00047-0;
RA Hu S.-H., Gehrmann J., Guddat L.W., Alewood P.F., Craik D.J., Martin J.L.;
RT "The 1.1 A crystal structure of the neuronal acetylcholine receptor
RT antagonist, alpha-conotoxin PnIA from Conus pennaceus.";
RL Structure 4:417-423(1996).
CC -!- FUNCTION: Alpha-conotoxins act on postsynaptic membranes, they bind to
CC the nicotinic acetylcholine receptors (nAChR) and thus inhibit them.
CC This toxin blocks mammalian alpha-3-beta-2/CHRNA3-CHRNB2 (IC(50)=7-68
CC nM) and alpha-7/CHRNA7 (IC(50)=253 nM) nAChRs (PubMed:8068627,
CC PubMed:10545176, PubMed:15929983, PubMed:22024738, PubMed:25101833). It
CC also shows a high inhibition on alpha-6/alpha-3-beta-2-beta-3
CC (CHRNA6/CHRNA3-CHRNB2-CHRNB3) (IC(50)=11 nM) and a low inhibition on
CC alpha-6-beta-4/CHRNA4-CHRNB4 (IC(50)>500 nM) (PubMed:22024738). It
CC interacts with a hydrophobic pocket between two acetylcholine receptor
CC subunits. In vivo, inhibits Ehrlich carcinoma growth and increase mouse
CC survival (PubMed:32272633). These effects are greatly enhanced when the
CC toxin is applied with the selective 12-lipoxygenase inhibitor baicalein
CC (PubMed:32272633). {ECO:0000269|PubMed:10545176,
CC ECO:0000269|PubMed:12734390, ECO:0000269|PubMed:15929983,
CC ECO:0000269|PubMed:22024738, ECO:0000269|PubMed:25101833,
CC ECO:0000269|PubMed:8068627}.
CC -!- INTERACTION:
CC P50984; Q8WSF8; Xeno; NbExp=2; IntAct=EBI-15553601, EBI-7179765;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:8068627}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom duct.
CC {ECO:0000305|PubMed:8068627}.
CC -!- DOMAIN: The cysteine framework is I (CC-C-C). Alpha4/7 pattern.
CC {ECO:0000305}.
CC -!- MISCELLANEOUS: The replacement of Ala-10 by a norleucine (A10Nle)
CC produces the more potent analog on alpha-7/CHRNA7 (IC(50)=4.3 nM) and
CC on alpha-3-beta-2/CHRNA3-CHRNB2 (IC(50)=0.7 nM) (PubMed:25101833).
CC {ECO:0000269|PubMed:25101833}.
CC -!- MISCELLANEOUS: This toxin shows no or very weak inhibition on alpha-2-
CC beta-2/CHRNA2-CHRNB2, alpha-3-beta-4/CHRNA3-CHRNB4, alpha-4-beta-
CC 2/CHRNA4-CHRNB2 and alpha-6/alpha-3-beta-4 nAChRs.
CC {ECO:0000269|PubMed:12734390, ECO:0000269|PubMed:15929983,
CC ECO:0000269|PubMed:22024738}.
CC -!- SIMILARITY: Belongs to the conotoxin A superfamily. {ECO:0000305}.
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DR PIR; A54877; A54877.
DR PDB; 1PEN; X-ray; 1.10 A; A=1-16.
DR PDB; 2BR8; X-ray; 2.40 A; F/G/H/I/J=1-16.
DR PDB; 7N1Z; NMR; -; A=1-16.
DR PDBsum; 1PEN; -.
DR PDBsum; 2BR8; -.
DR PDBsum; 7N1Z; -.
DR AlphaFoldDB; P50984; -.
DR SMR; P50984; -.
DR DIP; DIP-60493N; -.
DR IntAct; P50984; 2.
DR ConoServer; 75; Pni1.
DR ConoServer; 51; PnIA.
DR EvolutionaryTrace; P50984; -.
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; IPR018072; Conotoxin_a-typ_CS.
DR PROSITE; PS60014; ALPHA_CONOTOXIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylcholine receptor inhibiting toxin; Amidation;
KW Direct protein sequencing; Disulfide bond; Ion channel impairing toxin;
KW Neurotoxin; Postsynaptic neurotoxin; Secreted; Sulfation; Toxin.
FT PEPTIDE 1..16
FT /note="Alpha-conotoxin PnIA"
FT /evidence="ECO:0000269|PubMed:8068627"
FT /id="PRO_0000044462"
FT REGION 4..6
FT /note="Ser-Xaa-Pro motif, crucial for potent interaction
FT with nAChR"
FT /evidence="ECO:0000250|UniProtKB:P56636"
FT SITE 10
FT /note="Important for inhibitory potency on alpha-3-beta-
FT 2/CHRNA3-CHRNB2 nAChR; interacts with a hydrophobic pocket
FT between the two alpha-7/CHRNA7 subunits or between the
FT alpha-3 and the beta-2 subunits of alpha-3-beta-2/CHRNA3-
FT CHRNB2 nAChR"
FT /evidence="ECO:0000305|PubMed:10545176,
FT ECO:0000305|PubMed:25101833"
FT SITE 11
FT /note="Important for inhibitory potency on alpha-3-beta-
FT 2/CHRNA3-CHRNB2 and alpha-7/CHRNA7 nAChR"
FT /evidence="ECO:0000305|PubMed:10545176"
FT MOD_RES 15
FT /note="Sulfotyrosine"
FT /evidence="ECO:0000269|PubMed:10226369"
FT MOD_RES 16
FT /note="Cysteine amide"
FT /evidence="ECO:0000269|PubMed:8068627"
FT DISULFID 2..8
FT /evidence="ECO:0000269|PubMed:8068627,
FT ECO:0000269|PubMed:8740364, ECO:0000312|PDB:1PEN,
FT ECO:0000312|PDB:2BR8"
FT DISULFID 3..16
FT /evidence="ECO:0000269|PubMed:8068627,
FT ECO:0000269|PubMed:8740364, ECO:0000312|PDB:1PEN,
FT ECO:0000312|PDB:2BR8"
FT MUTAGEN 5
FT /note="L->R: In PnIA(L5R-A10L); 25-fold increase in
FT inhibitory potency on alpha-7/CHRNA7 and small increase in
FT inhibitory potency on alpha-3-beta-2/CHRNA3-CHRNB2."
FT /evidence="ECO:0000269|PubMed:17660751"
FT MUTAGEN 10
FT /note="A->L: Selectivity change from alpha-3-beta-2/CHRNA3-
FT CHRNB2 to alpha-7/CHRNA7. 20-fold increase in inhibitory
FT potency on alpha-7/CHRNA7, 7-10-fold decrease in inhibitory
FT potency on alpha-3-beta-2/CHRNA3-CHRNB2, and no change in
FT inhibitory potency on alpha-4-beta-2/CHRNA4-CHRNB2 nAChRs.
FT In PnIA(L5R-A10L); 25-fold increase in inhibitory potency
FT on alpha-7/CHRNA7 and small increase in inhibitory potency
FT on alpha-3-beta-2/CHRNA3-CHRNB2."
FT /evidence="ECO:0000269|PubMed:10545176,
FT ECO:0000269|PubMed:15929983, ECO:0000269|PubMed:17660751,
FT ECO:0000269|PubMed:25101833, ECO:0000269|PubMed:30025921"
FT MUTAGEN 11
FT /note="N->S: 7-fold decrease in inhibitory potency on
FT alpha-7/CHRNA7 and 25-fold decrease in inhibitory potency
FT on alpha-3-beta-2/CHRNA3-CHRNB2 nAChRs."
FT /evidence="ECO:0000269|PubMed:10545176"
FT HELIX 2..4
FT /evidence="ECO:0007829|PDB:1PEN"
FT HELIX 6..11
FT /evidence="ECO:0007829|PDB:1PEN"
FT TURN 13..15
FT /evidence="ECO:0007829|PDB:1PEN"
SQ SEQUENCE 16 AA; 1628 MW; 05310FF95EC99005 CRC64;
GCCSLPPCAA NNPDYC
