CAIMP_PANIM
ID CAIMP_PANIM Reviewed; 33 AA.
AC P59868;
DT 26-SEP-2003, integrated into UniProtKB/Swiss-Prot.
DT 26-SEP-2003, sequence version 1.
DT 03-AUG-2022, entry version 73.
DE RecName: Full=Imperacalcin {ECO:0000303|PubMed:27114612};
DE Short=IpCa {ECO:0000303|PubMed:27114612};
DE AltName: Full=Imperatoxin activator {ECO:0000303|PubMed:1334561};
DE AltName: Full=Imperatoxin-A {ECO:0000303|PubMed:1334561, ECO:0000303|PubMed:9108323};
DE Short=IpTxa {ECO:0000303|PubMed:1334561, ECO:0000303|PubMed:9108323};
OS Pandinus imperator (Emperor scorpion).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida;
OC Scorpiones; Iurida; Scorpionoidea; Scorpionidae; Pandininae; Pandinus.
OX NCBI_TaxID=55084;
RN [1]
RP PROTEIN SEQUENCE, SYNTHESIS, FUNCTION, AND SUBCELLULAR LOCATION.
RC TISSUE=Venom;
RX PubMed=9108323; DOI=10.1016/s0014-5793(97)00227-5;
RA Zamudio F.Z., Gurrola G.B., Arevalo C., Sreekumar R., Walker J.W.,
RA Valdivia H.H., Possani L.D.;
RT "Primary structure and synthesis of Imperatoxin A (IpTx(a)), a peptide
RT activator of Ca2+ release channels/ryanodine receptors.";
RL FEBS Lett. 405:385-389(1997).
RN [2]
RP IDENTIFICATION, AND FUNCTION.
RX PubMed=1334561; DOI=10.1073/pnas.89.24.12185;
RA Valdivia H.H., Kirby M.S., Lederer W.J., Coronado R.;
RT "Scorpion toxins targeted against the sarcoplasmic reticulum Ca(2+)-release
RT channel of skeletal and cardiac muscle.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:12185-12189(1992).
RN [3]
RP FUNCTION ON RYR1 AND RYR2.
RX PubMed=9565405; DOI=10.1085/jgp.111.5.679;
RA Tripathy A., Resch W., Xu L., Valdivia H.H., Meissner G.;
RT "Imperatoxin A induces subconductance states in Ca2+ release channels
RT (ryanodine receptors) of cardiac and skeletal muscle.";
RL J. Gen. Physiol. 111:679-690(1998).
RN [4]
RP FUNCTION ON RYR3.
RX PubMed=11867448; DOI=10.1016/s0006-3495(02)75487-8;
RA Nabhani T., Zhu X., Simeoni I., Sorrentino V., Valdivia H.H., Garcia J.;
RT "Imperatoxin A enhances Ca(2+) release in developing skeletal muscle
RT containing ryanodine receptor type 3.";
RL Biophys. J. 82:1319-1328(2002).
RN [5]
RP FUNCTION.
RX PubMed=14699105; DOI=10.1074/jbc.m310466200;
RA Dulhunty A.F., Curtis S.M., Watson S., Cengia L., Casarotto M.G.;
RT "Multiple actions of imperatoxin A on ryanodine receptors: interactions
RT with the II-III loop 'A' fragment.";
RL J. Biol. Chem. 279:11853-11862(2004).
RN [6]
RP FUNCTION, SYNTHESIS, NOMENCLATURE, AND 3D-STRUCTURE MODELING.
RX PubMed=27114612; DOI=10.1085/jgp.201511499;
RA Xiao L., Gurrola G.B., Zhang J., Valdivia C.R., SanMartin M., Zamudio F.Z.,
RA Zhang L., Possani L.D., Valdivia H.H.;
RT "Structure-function relationships of peptides forming the calcin family of
RT ryanodine receptor ligands.";
RL J. Gen. Physiol. 147:375-394(2016).
RN [7]
RP STRUCTURE BY NMR, DISULFIDE BONDS, AND MUTAGENESIS OF GLY-1; ASP-2; LEU-4;
RP PRO-5; HIS-6; LEU-7; LYS-8; ARG-9; LYS-11; ASP-13; ASN-14; ASP-15; GLY-18;
RP LYS-19; LYS-20; LYS-22; ARG-23; ARG-24; GLY-25; THR-26; ASN-27; GLU-29;
RP LYS-30; ARG-31 AND ARG-33.
RX PubMed=14535845; DOI=10.1042/bj20031192;
RA Lee C.W., Lee E.H., Takeuchi K., Takahashi H., Shimada I., Sato K.,
RA Shin S.Y., Kim do H., Kim J.I.;
RT "Molecular basis of the high-affinity activation of type 1 ryanodine
RT receptors by imperatoxin A.";
RL Biochem. J. 377:385-394(2004).
CC -!- FUNCTION: This toxin affects the activity of ryanodine receptors 1, 2
CC and 3 (RyR1, RyR2 and RyR3) (PubMed:1334561, PubMed:9565405,
CC PubMed:11867448). At lower concentrations the toxin increases full
CC openings of the RyRs, and at higher concentrations it inhibits full
CC openings and induces openings to subconductance levels (30% of the full
CC conductance state) and reduces the number of full conductance openings
CC (PubMed:9565405, PubMed:27114612). The different actions may be
CC attributed to the toxins binding at different sites on the RyRs, with
CC binding at a high-affinity site mediating the increase in full openings
CC and the induction of subconductance states evoked upon binding to a
CC lower-affinity site (PubMed:14699105). Furthermore, it triggers calcium
CC release from sarcoplasmic vesicles (11.7 nM are enough to induce a
CC sharp release, and 70% of the total calcium is released after toxin
CC (100 nM) addition) probably by acting as a cell-penetrating peptide
CC (CPP) (PubMed:1334561, PubMed:27114612). In addition, it has been shown
CC to dose-dependently stimulate ryanodine binding to RyR1 (EC(50)=8.7 nM)
CC (PubMed:27114612). It also augments the bell-shaped calcium-
CC [3H]ryanodine binding curve that is maximal at about 10 uM calcium
CC concentration (PubMed:27114612). It binds a different site as ryanodine
CC (PubMed:9565405). It acts synergistically with caffeine (By
CC similarity). In vivo, intracerebroventricular injection into mice
CC induces neurotoxic symptoms, followed by death (By similarity).
CC {ECO:0000250|UniProtKB:A0A1L4BJ42, ECO:0000250|UniProtKB:B8QG00,
CC ECO:0000250|UniProtKB:P60254, ECO:0000269|PubMed:11867448,
CC ECO:0000269|PubMed:1334561, ECO:0000269|PubMed:14699105,
CC ECO:0000269|PubMed:9565405}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:9108323}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:9108323}.
CC -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC structurally defines this protein as a knottin.
CC {ECO:0000269|PubMed:14535845}.
CC -!- SIMILARITY: Belongs to the scorpion calcin family. {ECO:0000305}.
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DR PDB; 1IE6; NMR; -; A=1-33.
DR PDBsum; 1IE6; -.
DR AlphaFoldDB; P59868; -.
DR BMRB; P59868; -.
DR SMR; P59868; -.
DR PRIDE; P59868; -.
DR EvolutionaryTrace; P59868; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0019855; F:calcium channel inhibitor activity; IEA:InterPro.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR InterPro; IPR012632; Scorpion_calcine.
DR Pfam; PF08099; Toxin_27; 1.
DR PROSITE; PS60028; SCORPION_CALCINE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Calcium channel impairing toxin; Direct protein sequencing;
KW Disulfide bond; Ion channel impairing toxin; Knottin; Neurotoxin;
KW Ryanodine-sensitive calcium-release channel impairing toxin; Secreted;
KW Toxin.
FT PEPTIDE 1..33
FT /note="Imperacalcin"
FT /evidence="ECO:0000269|PubMed:9108323"
FT /id="PRO_0000044949"
FT REGION 8..9
FT /note="Important for stimulation of [3H]ryanodine binding
FT to RYR1"
FT /evidence="ECO:0000269|PubMed:14535845"
FT REGION 19..20
FT /note="Important for stimulation of [3H]ryanodine binding
FT to RYR1"
FT /evidence="ECO:0000269|PubMed:14535845"
FT REGION 22..24
FT /note="Essential for stimulation of [3H]ryanodine binding
FT to RYR1"
FT /evidence="ECO:0000269|PubMed:14535845"
FT REGION 25..27
FT /note="Important for stimulation of [3H]ryanodine binding
FT to RYR1"
FT /evidence="ECO:0000269|PubMed:14535845"
FT SITE 6
FT /note="Important for stimulation of [3H]ryanodine binding
FT to RYR1"
FT /evidence="ECO:0000269|PubMed:14535845"
FT SITE 7
FT /note="Essential for stimulation of [3H]ryanodine binding
FT to RYR1"
FT /evidence="ECO:0000269|PubMed:14535845"
FT SITE 11
FT /note="Important for stimulation of [3H]ryanodine binding
FT to RYR1"
FT /evidence="ECO:0000269|PubMed:14535845"
FT SITE 30
FT /note="Important for stimulation of [3H]ryanodine binding
FT to RYR1"
FT /evidence="ECO:0000269|PubMed:14535845"
FT SITE 31
FT /note="Essential for stimulation of [3H]ryanodine binding
FT to RYR1"
FT /evidence="ECO:0000269|PubMed:14535845"
FT SITE 33
FT /note="Essential for stimulation of [3H]ryanodine binding
FT to RYR1"
FT /evidence="ECO:0000269|PubMed:14535845"
FT DISULFID 3..17
FT /evidence="ECO:0000269|PubMed:14535845,
FT ECO:0000312|PDB:1IE6"
FT DISULFID 10..21
FT /evidence="ECO:0000269|PubMed:14535845,
FT ECO:0000312|PDB:1IE6"
FT DISULFID 16..32
FT /evidence="ECO:0000269|PubMed:14535845,
FT ECO:0000312|PDB:1IE6"
FT MUTAGEN 1
FT /note="G->A: 1.18-fold decrease of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 2
FT /note="D->A: 2.33-fold increase of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 3
FT /note="C->A: Linear IpCa; Loss of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 4
FT /note="L->A: 1.93-fold decrease of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 5
FT /note="P->A: 1.43-fold decrease of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 6
FT /note="H->A: 20.72-fold decrease of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 7
FT /note="L->A: 97.51-fold decrease of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 8
FT /note="K->A: 4.60-fold decrease of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 9
FT /note="R->A: 25.62-fold decrease of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 10
FT /note="C->A: Linear IpCa; Loss of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 11
FT /note="K->A: 6.83-fold decrease of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 13
FT /note="D->A: 3.08-fold increase of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 14
FT /note="N->A: 1.14-fold decrease of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 15
FT /note="D->A: 2.73-fold increase of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 16
FT /note="C->A: Linear IpCa; Loss of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 17
FT /note="C->A: Linear IpCa; Loss of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 18
FT /note="G->A: 1.16-fold decrease of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 19
FT /note="K->A: 4.96-fold decrease of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 20
FT /note="K->A: 16.91-fold decrease of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 21
FT /note="C->A: Linear IpCa; Loss of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 22
FT /note="K->A: 69.92-fold decrease of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 23
FT /note="R->A: 418.48-fold decrease of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 24
FT /note="R->A: Loss of stimulation of [3H]ryanodine binding
FT to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 25
FT /note="G->A: 23.96-fold decrease of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 26
FT /note="T->A: 11.52-fold decrease of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 27
FT /note="N->A: 20.09-fold decrease of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 29
FT /note="E->A: 2.35-fold increase of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 30
FT /note="K->A: 21.69-fold decrease of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 31
FT /note="R->A: Loss of stimulation of [3H]ryanodine binding
FT to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 32
FT /note="C->A: Linear IpCa; Loss of stimulation of
FT [3H]ryanodine binding to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT MUTAGEN 33
FT /note="R->A: Loss of stimulation of [3H]ryanodine binding
FT to RYR1."
FT /evidence="ECO:0000269|PubMed:14535845"
FT HELIX 13..15
FT /evidence="ECO:0007829|PDB:1IE6"
FT STRAND 16..19
FT /evidence="ECO:0007829|PDB:1IE6"
FT STRAND 24..32
FT /evidence="ECO:0007829|PDB:1IE6"
SQ SEQUENCE 33 AA; 3764 MW; D0DF8EFFFE294537 CRC64;
GDCLPHLKRC KADNDCCGKK CKRRGTNAEK RCR
