3SE2_DENAN
ID 3SE2_DENAN Reviewed; 61 AA.
AC P0C1Z0; P01403;
DT 17-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 1.
DT 25-MAY-2022, entry version 65.
DE RecName: Full=Fasciculin-2 {ECO:0000303|PubMed:15299729, ECO:0000303|PubMed:6530667, ECO:0000303|PubMed:9013597};
DE Short=Fas-2;
DE Short=Fas2 {ECO:0000303|PubMed:9013597};
DE AltName: Full=Acetylcholinesterase toxin F-VII {ECO:0000303|PubMed:4123919};
DE AltName: Full=Fasciculin-II {ECO:0000303|PubMed:11053835};
DE Short=FAS-II {ECO:0000303|PubMed:11053835};
DE AltName: Full=Toxin TA1;
OS Dendroaspis angusticeps (Eastern green mamba) (Naja angusticeps).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Lepidosauria; Squamata; Bifurcata; Unidentata; Episquamata; Toxicofera;
OC Serpentes; Colubroidea; Elapidae; Elapinae; Dendroaspis.
OX NCBI_TaxID=8618;
RN [1]
RP PROTEIN SEQUENCE, AND SUBCELLULAR LOCATION.
RC TISSUE=Venom;
RX PubMed=4123919; DOI=10.1016/s0021-9258(19)43651-x;
RA Viljoen C.C., Botes D.P.;
RT "Snake venom toxins. The purification and amino acid sequence of toxin F-
RT VII from Dendroaspis angusticeps venom.";
RL J. Biol. Chem. 248:4915-4919(1973).
RN [2]
RP FUNCTION.
RX PubMed=6530667;
RA Karlsson E., Mbugua P.M., Rodriguez-Ithurralde D.;
RT "Fasciculins, anticholinesterase toxins from the venom of the green mamba
RT Dendroaspis angusticeps.";
RL J. Physiol. (Paris) 79:232-240(1984).
RN [3]
RP SYNTHESIS, AND MUTAGENESIS OF 8-THR-THR-9; ARG-11; ARG-24; LYS-25; ARG-27;
RP ARG-28; HIS-29; PRO-30; PRO-31; LYS-32; MET-33; 34-VAL-LEU-35; ASP-45 AND
RP LYS-51.
RX PubMed=9013597; DOI=10.1074/jbc.272.6.3502;
RA Marchot P., Prowse C.N., Kanter J., Camp S., Ackermann E.J., Radic Z.,
RA Bougis P.E., Taylor P.;
RT "Expression and activity of mutants of fasciculin, a peptidic
RT acetylcholinesterase inhibitor from mamba venom.";
RL J. Biol. Chem. 272:3502-3510(1997).
RN [4]
RP MUTAGENESIS OF THR-8; THR-9; ARG-11; HIS-29 AND LYS-32.
RX PubMed=19643977; DOI=10.1093/protein/gzp045;
RA Sharabi O., Peleg Y., Mashiach E., Vardy E., Ashani Y., Silman I.,
RA Sussman J.L., Shifman J.M.;
RT "Design, expression and characterization of mutants of fasciculin optimized
RT for interaction with its target, acetylcholinesterase.";
RL Protein Eng. Des. Sel. 22:641-648(2009).
RN [5]
RP PRELIMINARY CRYSTALLIZATION.
RX PubMed=2592383; DOI=10.1016/s0021-9258(19)30094-8;
RA le Du M.H., Marchot P., Bougis P.E., Fontecilla-Camps J.-C.;
RT "Crystals of fasciculin 2 from green mamba snake venom. Preparation and
RT preliminary X-ray analysis.";
RL J. Biol. Chem. 264:21401-21402(1989).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS), AND DISULFIDE BONDS.
RX PubMed=15299729; DOI=10.1107/s0907444995007517;
RA le Du M.-H., Housset D., Marchot P., Bougis P.E., Navaza J.,
RA Fontecilla-Camps J.-C.;
RT "Structure of fasciculin 2 from green mamba snake venom: evidence for
RT unusual loop flexibility.";
RL Acta Crystallogr. D 52:87-92(1996).
RN [7]
RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) IN COMPLEX WITH ACHE, AND DISULFIDE
RP BONDS.
RX PubMed=8747462; DOI=10.1016/s0969-2126(01)00273-8;
RA Harel M., Kleywegt G.J., Ravelli R.B., Silman I., Sussman J.L.;
RT "Crystal structure of an acetylcholinesterase-fasciculin complex:
RT interaction of a three-fingered toxin from snake venom with its target.";
RL Structure 3:1355-1366(1995).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (3.2 ANGSTROMS) IN COMPLEX WITH ACHE, AND DISULFIDE
RP BONDS.
RX PubMed=8521480; DOI=10.1016/0092-8674(95)90128-0;
RA Bourne Y., Taylor P., Marchot P.;
RT "Acetylcholinesterase inhibition by fasciculin: crystal structure of the
RT complex.";
RL Cell 83:503-512(1995).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.76 ANGSTROMS) IN COMPLEX WITH ACHE, AND DISULFIDE
RP BOND.
RX PubMed=11053835; DOI=10.1107/s0907444900010659;
RA Kryger G., Harel M., Giles K., Toker L., Velan B., Lazar A., Kronman C.,
RA Barak D., Ariel N., Shafferman A., Silman I., Sussman J.L.;
RT "Structures of recombinant native and E202Q mutant human
RT acetylcholinesterase complexed with the snake-venom toxin fasciculin-II.";
RL Acta Crystallogr. D 56:1385-1394(2000).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS), AND DISULFIDE BOND.
RX PubMed=12505979; DOI=10.1093/emboj/cdg005;
RA Bourne Y., Taylor P., Radic Z., Marchot P.;
RT "Structural insights into ligand interactions at the acetylcholinesterase
RT peripheral anionic site.";
RL EMBO J. 22:1-12(2003).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.95 ANGSTROMS) IN COMPLEX WITH ACHE, AND DISULFIDE
RP BOND.
RX PubMed=20408548; DOI=10.1021/jm901853b;
RA Carletti E., Colletier J.P., Dupeux F., Trovaslet M., Masson P., Nachon F.;
RT "Structural evidence that human acetylcholinesterase inhibited by tabun
RT ages through O-dealkylation.";
RL J. Med. Chem. 53:4002-4008(2010).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) IN COMPLEX WITH ACHE, AND DISULFIDE
RP BOND.
RX PubMed=23035744; DOI=10.1021/jm300871x;
RA Cheung J., Rudolph M.J., Burshteyn F., Cassidy M.S., Gary E.N., Love J.,
RA Franklin M.C., Height J.J.;
RT "Structures of human acetylcholinesterase in complex with pharmacologically
RT important ligands.";
RL J. Med. Chem. 55:10282-10286(2012).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (3.10 ANGSTROMS) IN COMPLEX WITH ACHE, AND DISULFIDE
RP BOND.
RX PubMed=23679855; DOI=10.1042/bj20130013;
RA Nachon F., Carletti E., Ronco C., Trovaslet M., Nicolet Y., Jean L.,
RA Renard P.Y.;
RT "Crystal structures of human cholinesterases in complex with huprine W and
RT tacrine: elements of specificity for anti-Alzheimer's drugs targeting
RT acetyl- and butyryl-cholinesterase.";
RL Biochem. J. 453:393-399(2013).
CC -!- FUNCTION: Interferes with neuromuscular transmission by inhibiting the
CC enzyme acetylcholinesterase (AChE) present at the neuromuscular
CC junction. It selectively binds and inhibits with a 1:1 stoichiometry
CC the mammalian and electric fish AChE at picomolar concentrations. It is
CC highly specific for the peripheral site of AChE and blocks the entry of
CC acetylcholine into the active site of the enzyme (through the Met-33
CC residue), thereby preventing its breakdown. It has been called
CC fasciculin since after injection into mice it causes severe,
CC generalized and long-lasting (5-7 hours) fasciculations.
CC {ECO:0000269|PubMed:6530667}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:4123919}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland. {ECO:0000305}.
CC -!- TOXIC DOSE: LD(50) is >20 mg/kg by intravenous injection.
CC -!- SIMILARITY: Belongs to the snake three-finger toxin family. Short-chain
CC subfamily. Acn-esterase inhibitor sub-subfamily. {ECO:0000305}.
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DR PIR; A01674; T4EP1A.
DR PDB; 1B41; X-ray; 2.76 A; B=1-61.
DR PDB; 1F8U; X-ray; 2.90 A; B=1-61.
DR PDB; 1FSC; X-ray; 2.00 A; A=1-61.
DR PDB; 1FSS; X-ray; 3.00 A; B=1-61.
DR PDB; 1KU6; X-ray; 2.50 A; B=1-61.
DR PDB; 1MAH; X-ray; 3.20 A; F=1-61.
DR PDB; 2X8B; X-ray; 2.95 A; B=1-61.
DR PDB; 4BDT; X-ray; 3.10 A; B=1-61.
DR PDB; 4EY8; X-ray; 2.60 A; B=1-61.
DR PDBsum; 1B41; -.
DR PDBsum; 1F8U; -.
DR PDBsum; 1FSC; -.
DR PDBsum; 1FSS; -.
DR PDBsum; 1KU6; -.
DR PDBsum; 1MAH; -.
DR PDBsum; 2X8B; -.
DR PDBsum; 4BDT; -.
DR PDBsum; 4EY8; -.
DR AlphaFoldDB; P0C1Z0; -.
DR SMR; P0C1Z0; -.
DR EvolutionaryTrace; P0C1Z0; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR Gene3D; 2.10.60.10; -; 1.
DR InterPro; IPR045860; Snake_toxin-like_sf.
DR InterPro; IPR018354; Snake_toxin_con_site.
DR SUPFAM; SSF57302; SSF57302; 1.
DR PROSITE; PS00272; SNAKE_TOXIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Direct protein sequencing; Disulfide bond; Secreted; Toxin.
FT CHAIN 1..61
FT /note="Fasciculin-2"
FT /evidence="ECO:0000269|PubMed:4123919"
FT /id="PRO_0000253031"
FT SITE 33
FT /note="Blocks the entrance of the active site gorge of
FT hAChE"
FT /evidence="ECO:0000303|PubMed:23679855"
FT DISULFID 3..22
FT /evidence="ECO:0000269|PubMed:11053835,
FT ECO:0000269|PubMed:12505979, ECO:0000269|PubMed:15299729,
FT ECO:0000269|PubMed:20408548, ECO:0000269|PubMed:23035744,
FT ECO:0000269|PubMed:23679855, ECO:0000269|PubMed:8521480,
FT ECO:0000269|PubMed:8747462, ECO:0000312|PDB:1B41,
FT ECO:0000312|PDB:1F8U, ECO:0000312|PDB:1FSC,
FT ECO:0000312|PDB:1FSS, ECO:0000312|PDB:1KU6,
FT ECO:0000312|PDB:1MAH, ECO:0000312|PDB:2X8B,
FT ECO:0000312|PDB:4BDT, ECO:0000312|PDB:4EY8"
FT DISULFID 17..39
FT /evidence="ECO:0000269|PubMed:11053835,
FT ECO:0000269|PubMed:12505979, ECO:0000269|PubMed:15299729,
FT ECO:0000269|PubMed:20408548, ECO:0000269|PubMed:23035744,
FT ECO:0000269|PubMed:23679855, ECO:0000269|PubMed:8521480,
FT ECO:0000269|PubMed:8747462, ECO:0000312|PDB:1B41,
FT ECO:0000312|PDB:1F8U, ECO:0000312|PDB:1FSC,
FT ECO:0000312|PDB:1FSS, ECO:0000312|PDB:1KU6,
FT ECO:0000312|PDB:1MAH, ECO:0000312|PDB:2X8B,
FT ECO:0000312|PDB:4BDT, ECO:0000312|PDB:4EY8"
FT DISULFID 41..52
FT /evidence="ECO:0000269|PubMed:11053835,
FT ECO:0000269|PubMed:12505979, ECO:0000269|PubMed:15299729,
FT ECO:0000269|PubMed:20408548, ECO:0000269|PubMed:23035744,
FT ECO:0000269|PubMed:23679855, ECO:0000269|PubMed:8521480,
FT ECO:0000269|PubMed:8747462, ECO:0000312|PDB:1B41,
FT ECO:0000312|PDB:1F8U, ECO:0000312|PDB:1FSC,
FT ECO:0000312|PDB:1FSS, ECO:0000312|PDB:1KU6,
FT ECO:0000312|PDB:1MAH, ECO:0000312|PDB:2X8B,
FT ECO:0000312|PDB:4BDT, ECO:0000312|PDB:4EY8"
FT DISULFID 53..59
FT /evidence="ECO:0000269|PubMed:11053835,
FT ECO:0000269|PubMed:12505979, ECO:0000269|PubMed:15299729,
FT ECO:0000269|PubMed:20408548, ECO:0000269|PubMed:23035744,
FT ECO:0000269|PubMed:23679855, ECO:0000269|PubMed:8521480,
FT ECO:0000269|PubMed:8747462, ECO:0000312|PDB:1B41,
FT ECO:0000312|PDB:1F8U, ECO:0000312|PDB:1FSC,
FT ECO:0000312|PDB:1FSS, ECO:0000312|PDB:1KU6,
FT ECO:0000312|PDB:1MAH, ECO:0000312|PDB:2X8B,
FT ECO:0000312|PDB:4BDT, ECO:0000312|PDB:4EY8"
FT MUTAGEN 8..9
FT /note="TT->AA: 18-fold increase in inhibition potency."
FT /evidence="ECO:0000269|PubMed:9013597"
FT MUTAGEN 8
FT /note="T->V: 2.5-fold increase in affinity for TcAChE. 2.1-
FT fold decrease in affinity for TcAChE; when associated with
FT N-9. 1.9-fold increase in affinity for TcAChE; when
FT associated with N-9, K-11 and R-29 [FasDesK32]. 3.9-fold
FT decrease in affinity for TcAChE; when associated with N-9,
FT K-11, R-29 and R-32 [FasDes]."
FT /evidence="ECO:0000269|PubMed:19643977"
FT MUTAGEN 9
FT /note="T->N: 9.0-fold decrease in affinity for TcAChE. 2.1-
FT fold decrease in affinity for TcAChE; when associated with
FT V-8. 1.9-fold increase in affinity for TcAChE; when
FT associated with V-8, K-11 and R-29 [FasDesK32]. 3.9-fold
FT decrease in affinity for TcAChE; when associated with V-8,
FT K-11, R-29 and R-32 [FasDes]."
FT /evidence="ECO:0000269|PubMed:19643977"
FT MUTAGEN 11
FT /note="R->K: 1.7-fold decrease in affinity for TcAChE. 1.9-
FT fold increase in affinity for TcAChE; when associated with
FT V-8, N-9 and R-29 [FasDesK32]. 3.9-fold decrease in
FT affinity for TcAChE; when associated with V-8, N-9, R-29
FT and R-32 [FasDes]."
FT /evidence="ECO:0000269|PubMed:19643977"
FT MUTAGEN 11
FT /note="R->Q: 6-fold increase in inhibition potency."
FT /evidence="ECO:0000269|PubMed:9013597"
FT MUTAGEN 24
FT /note="R->T: 13-fold decrease in inhibition potency."
FT /evidence="ECO:0000269|PubMed:9013597"
FT MUTAGEN 25
FT /note="K->L: No significant difference in inhibition
FT potency."
FT /evidence="ECO:0000269|PubMed:9013597"
FT MUTAGEN 27
FT /note="R->W: 49-fold decrease in inhibition potency."
FT /evidence="ECO:0000269|PubMed:9013597"
FT MUTAGEN 28
FT /note="R->D: No significant difference in inhibition
FT potency."
FT /evidence="ECO:0000269|PubMed:9013597"
FT MUTAGEN 29
FT /note="H->D: 73-fold increase in inhibition potency."
FT /evidence="ECO:0000269|PubMed:9013597"
FT MUTAGEN 29
FT /note="H->R: 6.0-fold increase in affinity for TcAChE. 1.9-
FT fold increase in affinity for TcAChE; when associated with
FT V-8, N-9 and K-11 [FasDesK32]. 3.9-fold decrease in
FT affinity for TcAChE; when associated with V-8, N-9, K-11
FT and R-32 [FasDes]."
FT /evidence="ECO:0000269|PubMed:19643977"
FT MUTAGEN 30
FT /note="Missing: 192-fold decrease in inhibition potency."
FT /evidence="ECO:0000269|PubMed:9013597"
FT MUTAGEN 31
FT /note="P->R: 625-fold decrease in inhibition potency."
FT /evidence="ECO:0000269|PubMed:9013597"
FT MUTAGEN 32
FT /note="K->G: 3-fold decrease in inhibition potency."
FT /evidence="ECO:0000269|PubMed:9013597"
FT MUTAGEN 32
FT /note="K->R: 7.4-fold decrease in affinity for TcAChE. 3.9-
FT fold decrease in affinity for TcAChE; when associated with
FT V-8, N-9, K-11 and R-29 [FasDes]."
FT /evidence="ECO:0000269|PubMed:19643977"
FT MUTAGEN 33
FT /note="M->A: 8-fold decrease in inhibition potency."
FT /evidence="ECO:0000269|PubMed:9013597"
FT MUTAGEN 34..35
FT /note="VL->AA: No significant difference in inhibition
FT potency."
FT /evidence="ECO:0000269|PubMed:9013597"
FT MUTAGEN 45
FT /note="D->K: No significant difference in inhibition
FT potency."
FT /evidence="ECO:0000269|PubMed:9013597"
FT MUTAGEN 51
FT /note="K->S: No significant difference in inhibition
FT potency."
FT /evidence="ECO:0000269|PubMed:9013597"
FT STRAND 2..6
FT /evidence="ECO:0007829|PDB:1FSC"
FT STRAND 8..10
FT /evidence="ECO:0007829|PDB:1FSC"
FT STRAND 13..16
FT /evidence="ECO:0007829|PDB:1FSC"
FT STRAND 22..31
FT /evidence="ECO:0007829|PDB:1FSC"
FT STRAND 34..40
FT /evidence="ECO:0007829|PDB:1FSC"
FT STRAND 46..53
FT /evidence="ECO:0007829|PDB:1FSC"
FT TURN 57..60
FT /evidence="ECO:0007829|PDB:1FSC"
SQ SEQUENCE 61 AA; 6758 MW; 50A38EF3633C383F CRC64;
TMCYSHTTTS RAILTNCGEN SCYRKSRRHP PKMVLGRGCG CPPGDDNLEV KCCTSPDKCN
Y
