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 22-FEB-2023, entry version 67. 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}. 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 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; CD59; 1. DR InterPro; IPR045860; Snake_toxin-like_sf. DR InterPro; IPR018354; Snake_toxin_con_site. DR SUPFAM; SSF57302; Snake toxin-like; 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. FT 2.1-fold decrease in affinity for TcAChE; when associated FT with 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. FT 2.1-fold decrease in affinity for TcAChE; when associated FT with 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. FT 1.9-fold increase in affinity for TcAChE; when associated FT with 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. FT 1.9-fold increase in affinity for TcAChE; when associated FT with 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. FT 3.9-fold decrease in affinity for TcAChE; when associated FT with 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 //