CA11_CONLT
ID CA11_CONLT Reviewed; 68 AA.
AC Q2I2R8;
DT 15-JAN-2008, integrated into UniProtKB/Swiss-Prot.
DT 07-MAR-2006, sequence version 1.
DT 25-MAY-2022, entry version 44.
DE RecName: Full=Alpha-conotoxin Lt1a {ECO:0000303|PubMed:34523332};
DE AltName: Full=Alpha-conotoxin Lt1.1 {ECO:0000303|PubMed:16908117};
DE Flags: Precursor;
OS Conus litteratus (Lettered cone).
OC Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Elisaconus.
OX NCBI_TaxID=89445;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Venom duct;
RX PubMed=16908117; DOI=10.1016/j.ygeno.2006.06.014;
RA Pi C., Liu J., Peng C., Liu Y., Jiang X., Zhao Y., Tang S., Wang L.,
RA Dong M., Chen S., Xu A.;
RT "Diversity and evolution of conotoxins based on gene expression profiling
RT of Conus litteratus.";
RL Genomics 88:809-819(2006).
RN [2]
RP FUNCTION, SYNTHESIS OF 49-64, PROBABLE AMIDATION AT CYS-64, 3D-STRUCTURE
RP MODELING IN COMPLEX WITH ALPHA-3-BETA-2 NACHRS, AND MUTAGENESIS OF ALA-52
RP AND ALA-54.
RX PubMed=20145249; DOI=10.1074/jbc.m109.079012;
RA Luo S., Akondi K.B., Zhangsun D., Wu Y., Zhu X., Hu Y., Christensen S.,
RA Dowell C., Daly N.L., Craik D.J., Wang C.I., Lewis R.J., Alewood P.F.,
RA Michael McIntosh J.;
RT "Atypical alpha-conotoxin LtIA from Conus litteratus targets a novel
RT microsite of the alpha3beta2 nicotinic receptor.";
RL J. Biol. Chem. 285:12355-12366(2010).
RN [3]
RP FUNCTION, AND BIOTECHNOLOGY.
RX PubMed=34523332; DOI=10.1021/acschemneuro.1c00392;
RA Yang Y., Tan Y., Zhangsun D., Zhu X., Luo S.;
RT "Design, synthesis, and activity of an alpha-conotoxin LtIA fluorescent
RT analogue.";
RL ACS Chem. Neurosci. 12:3662-3671(2021).
CC -!- FUNCTION: Alpha-conotoxins act on postsynaptic membranes, they bind to
CC the nicotinic acetylcholine receptors (nAChR) and thus inhibit them.
CC This toxin potently and selectively blocks rat alpha-3-beta-2/CHRNA3-
CC CHRNB2 nAChRs (IC(50)=9.8-22.95 nM) (PubMed:20145249, PubMed:34523332).
CC Also shows a moderate block on rat alpha-6/alpha-3-beta-2-beta-3
CC (CHRNA6/CHRNA3-CHRNB2-CHRNB3) nAChRs (IC(50)=84.4 nM), and a weak
CC activity on rat alpha-6/alpha-3-beta-4 (CHRNA6/CHRNA3-CHRNB4) nAChRs
CC (IC(50)~6 uM) (PubMed:20145249). The block of alpha-3-beta-2/CHRNA3-
CC CHRNB2 nAChRs is rapidly reversible (PubMed:20145249). It prevents
CC alpha-conotoxin MII from blocking alpha-3-beta-2/CHRNA3-CHRNB2 nAChRs,
CC suggesting that both toxins have overlapping binding sites
CC (PubMed:20145249). In addition, this toxin shows a distinct nAChR
CC binding mode from other alpha-conotoxins (PubMed:20145249). It potently
CC blocks alpha-3-beta-2/CHRNA3-CHRNB2 nAChRs, although it lacks the
CC highly conserved motif Ser-Xaa-Pro motif found in many other alpha-
CC conotoxins to be crucial for potent nAChR interaction
CC (PubMed:20145249). It seems to show relative flexibility in solution,
CC wich is consistent with the absence of the conserved Ser and Pro
CC residues that likely have a structure-defining role in other alpha-
CC conotoxins (PubMed:20145249). Molecular docking simulations also
CC suggest that this toxin has a surprisingly shallow binding site on the
CC alpha-3-beta-2/CHRNA3-CHRNB2 nAChRs (PubMed:20145249).
CC {ECO:0000269|PubMed:20145249, ECO:0000269|PubMed:34523332}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305|PubMed:16908117}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom duct.
CC {ECO:0000305|PubMed:16908117}.
CC -!- DOMAIN: The cysteine framework is I (CC-C-C). Alpha4/7 pattern.
CC {ECO:0000305|PubMed:16908117}.
CC -!- BIOTECHNOLOGY: The fluorescent analog of LtIA (LtIA-F) is a highly
CC selective molecule targeting alpha-3-beta-2/CHRNA3-CHRNB2 nAChR that
CC could be used as a molecular probe for the study of the structure,
CC function, and distribution of this receptor in live systems. It
CC displays a ~4-fold decrease in potency towards alpha-3-beta-2/CHRNA3-
CC CHRNB2 compared with native LtIA without a change in selectivity.
CC {ECO:0000269|PubMed:34523332}.
CC -!- MISCELLANEOUS: Does not show activity on alpha-9-alpha-10/CHRNA9-
CC CHRNA10, alpha-4-beta-2/CHRNA4-CHRNB2, alpha-4-beta-4/CHRNA4-CHRNB4,
CC alpha-3-beta-4/CHRNA3-CHRNB4, alpha-2-beta-2/CHRNA2-CHRNB2, alpha-2-
CC beta-4/CHRNA2-CHRNB4, alpha-1-beta-1-delta-epsilon/CHRNA1-CHRNB1-CHRND-
CC CHRNE, and alpha-7/CHRNA7. {ECO:0000269|PubMed:20145249}.
CC -!- SIMILARITY: Belongs to the conotoxin A superfamily. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; DQ345364; ABC74972.1; -; mRNA.
DR AlphaFoldDB; Q2I2R8; -.
DR ConoServer; 1151; LtIA 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: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 Pfam; PF07365; Toxin_8; 1.
PE 1: Evidence at protein level;
KW Acetylcholine receptor inhibiting toxin; Amidation; Disulfide bond;
KW Ion channel impairing toxin; Neurotoxin; Postsynaptic neurotoxin; Secreted;
KW Signal; Toxin.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT PROPEP 22..48
FT /evidence="ECO:0000305|PubMed:20145249"
FT /id="PRO_0000315417"
FT PEPTIDE 49..64
FT /note="Alpha-conotoxin Lt1a"
FT /evidence="ECO:0000305|PubMed:20145249"
FT /id="PRO_0000315418"
FT PROPEP 66..68
FT /evidence="ECO:0000305"
FT /id="PRO_0000392694"
FT REGION 52..54
FT /note="Lacks the Ser-Xaa-Pro motif that is crucial for
FT potent interaction with nAChR"
FT /evidence="ECO:0000305"
FT REGION 52..54
FT /note="Ser-Xaa-Pro motif, crucial for potent interaction
FT with nAChR"
FT /evidence="ECO:0000250|UniProtKB:P56636"
FT MOD_RES 64
FT /note="Cysteine amide"
FT /evidence="ECO:0000305|PubMed:20145249"
FT DISULFID 50..56
FT /evidence="ECO:0000250|UniProtKB:P56636,
FT ECO:0000305|PubMed:20145249"
FT DISULFID 51..64
FT /evidence="ECO:0000250|UniProtKB:P56636,
FT ECO:0000305|PubMed:20145249"
FT MUTAGEN 52
FT /note="A->S: 3-fold decrease in ability to block alpha-3-
FT beta-2/CHRNA3-CHRNB2 nAChRs. 2.4-fold decrease in ability
FT to block alpha-3-beta-2/CHRNA3-CHRNB2 nAChRs; when
FT associated with P-54."
FT /evidence="ECO:0000269|PubMed:20145249"
FT MUTAGEN 54
FT /note="A->P: 2.4-fold decrease in ability to block alpha-3-
FT beta-2/CHRNA3-CHRNB2 nAChRs; when associated with S-52."
FT /evidence="ECO:0000269|PubMed:20145249"
SQ SEQUENCE 68 AA; 7155 MW; 30B30442453B2F3D CRC64;
MGMRMMFIMF MLVVLATTVV TFTSDRALDA MNAAASNKAS RLIALAVRGC CARAACAGIH
QELCGGGR
