LATA_LATTR
ID LATA_LATTR Reviewed; 1401 AA.
AC P23631; O76456; Q25328;
DT 01-NOV-1991, integrated into UniProtKB/Swiss-Prot.
DT 11-JUL-2002, sequence version 2.
DT 25-MAY-2022, entry version 115.
DE RecName: Full=Alpha-latrotoxin-Lt1a {ECO:0000305};
DE Short=Alpha-LTX-Lt1a {ECO:0000305};
DE AltName: Full=Alpha-latrotoxin {ECO:0000303|PubMed:1977615};
DE Short=Alpha-LTX {ECO:0000303|PubMed:1977615};
DE Flags: Precursor;
OS Latrodectus tredecimguttatus (Mediterranean black widow spider)
OS (Latrodectus mactans tredecimguttatus).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Chelicerata; Arachnida; Araneae;
OC Araneomorphae; Entelegynae; Araneoidea; Theridiidae; Latrodectus.
OX NCBI_TaxID=6925;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Venom gland;
RX PubMed=1977615; DOI=10.1016/0014-5793(90)81250-r;
RA Kiyatkin N.I., Dulubova I.E., Chekhovskaya I.A., Grishin E.V.;
RT "Cloning and structure of cDNA encoding alpha-latrotoxin from black widow
RT spider venom.";
RL FEBS Lett. 270:127-131(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 21-1197, FUNCTION, MUTAGENESIS OF CYS-34;
RP CYS-91; CYS-413 AND LEU-448, AND RECOMBINANT EXPRESSION.
RC TISSUE=Venom gland;
RX PubMed=9799228; DOI=10.1093/emboj/17.21.6188;
RA Ichtchenko K., Khvotchev M., Kiyatkin N., Simpson L., Sugita S.,
RA Suedhof T.C.;
RT "Alpha-latrotoxin action probed with recombinant toxin: receptors recruit
RT alpha-latrotoxin but do not transduce an exocytotic signal.";
RL EMBO J. 17:6188-6199(1998).
RN [3]
RP PARTIAL PROTEIN SEQUENCE, AND SUBCELLULAR LOCATION.
RC TISSUE=Venom;
RX PubMed=1888339;
RA Volkova T.M., Galkina T.G., Kudelin A.B., Nazimov I.V., Grishin E.V.;
RT "Structure of tryptic fragments of a neurotoxin from black widow spider
RT venom.";
RL Bioorg. Khim. 17:437-441(1991).
RN [4]
RP PROTEIN SEQUENCE OF 21-39, TOXIC DOSE, AND SUBCELLULAR LOCATION.
RX PubMed=9792186; DOI=10.1016/s0041-0101(98)00162-7;
RA Grishin E.V.;
RT "Black widow spider toxins: the present and the future.";
RL Toxicon 36:1693-1701(1998).
RN [5]
RP FUNCTION, AND ALPHA-LATROTOXIN RECEPTOR.
RX PubMed=7592578; DOI=10.1074/jbc.270.41.23903;
RA Davletov B.A., Krasnoperov V., Hata Y., Petrenko A.G., Suedhof T.C.;
RT "High affinity binding of alpha-latrotoxin to recombinant neurexin I
RT alpha.";
RL J. Biol. Chem. 270:23903-23905(1995).
RN [6]
RP FUNCTION, AND ALPHA-LATROTOXIN RECEPTOR.
RX PubMed=8798521; DOI=10.1074/jbc.271.38.23239;
RA Davletov B.A., Shamotienko O.G., Lelianova V.G., Grishin E.V.,
RA Ushkaryov Y.A.;
RT "Isolation and biochemical characterization of a Ca2+-independent alpha-
RT latrotoxin-binding protein.";
RL J. Biol. Chem. 271:23239-23245(1996).
RN [7]
RP SUBUNIT, AND SUBCELLULAR LOCATION.
RX PubMed=10865132; DOI=10.1016/s0300-9084(00)00199-1;
RA Ashton A.C., Rahman M.A., Volynski K.E., Manser C., Orlova E.V.,
RA Matsushita H., Davletov B.A., van Heel M., Grishin E.V., Ushkaryov Y.A.;
RT "Tetramerisation of alpha-latrotoxin by divalent cations is responsible for
RT toxin-induced non-vesicular release and contributes to the Ca(2+)-dependent
RT vesicular exocytosis from synaptosomes.";
RL Biochimie 82:453-468(2000).
RN [8]
RP EPITOPE FOR 4C4.1 MONOCLONAL ANTIBODY.
RX PubMed=11086220; DOI=10.1016/s0300-9084(00)01170-6;
RA Pescatori M., Grasso A.;
RT "Characterization of the epitope for 4C4.1 mAb on alpha-latrotoxin using
RT phage display-peptide libraries: prevention of toxin-dependent 45Ca(2+)
RT uptake in non-neuronal human embryonic cells transiently expressing
RT latrophilin.";
RL Biochimie 82:909-914(2000).
RN [9]
RP FUNCTION, AND SUBUNIT.
RX PubMed=11572875; DOI=10.1074/jbc.m108088200;
RA Ashton A.C., Volynski K.E., Lelianova V.G., Orlova E.V., Van Renterghem C.,
RA Canepari M., Seagar M., Ushkaryov Y.A.;
RT "alpha-latrotoxin, acting via two Ca2+-dependent pathways, triggers
RT exocytosis of two pools of synaptic vesicles.";
RL J. Biol. Chem. 276:44695-44703(2001).
RN [10]
RP FUNCTION, AND ALPHA-LATROTOXIN RECEPTOR.
RX PubMed=12110683; DOI=10.1074/jbc.m205478200;
RA Krasnoperov V., Bittner M.A., Mo W., Buryanovsky L., Neubert T.A.,
RA Holz R.W., Ichtchenko K., Petrenko A.G.;
RT "Protein-tyrosine phosphatase-sigma is a novel member of the functional
RT family of alpha-latrotoxin receptors.";
RL J. Biol. Chem. 277:35887-35895(2002).
RN [11]
RP FUNCTION.
RX PubMed=12764091; DOI=10.1523/jneurosci.23-10-04044.2003;
RA Capogna M., Volynski K.E., Emptage N.J., Ushkaryov Y.A.;
RT "The alpha-latrotoxin mutant LTXN4C enhances spontaneous and evoked
RT transmitter release in CA3 pyramidal neurons.";
RL J. Neurosci. 23:4044-4053(2003).
RN [12]
RP BIOTECHNOLOGY.
RX PubMed=22069721; DOI=10.3390/toxins3050489;
RA Mesngon M., McNutt P.;
RT "Alpha-latrotoxin rescues SNAP-25 from BoNT/A-mediated proteolysis in
RT embryonic stem cell-derived neurons.";
RL Toxins 3:489-503(2011).
RN [13]
RP REVIEW.
RX PubMed=18064415; DOI=10.1007/978-3-540-74805-2_7;
RA Ushkaryov Y.A., Rohou A., Sugita S.;
RT "Alpha-latrotoxin and its receptors.";
RL Handb. Exp. Pharmacol. 184:171-206(2008).
RN [14]
RP REVIEW, AND BIOTECHNOLOGY.
RX PubMed=19682210; DOI=10.1111/j.1471-4159.2009.06329.x;
RA Silva J.P., Suckling J., Ushkaryov Y.;
RT "Penelope's web: using alpha-latrotoxin to untangle the mysteries of
RT exocytosis.";
RL J. Neurochem. 111:275-290(2009).
RN [15]
RP STRUCTURE BY ELECTRON MICROSCOPY, PROBABLE DISULFIDE BOND, AND SUBUNIT.
RX PubMed=10625427; DOI=10.1038/71247;
RA Orlova E.V., Rahman M.A., Gowen B., Volynski K.E., Ashton A.C., Manser C.,
RA van Heel M., Ushkaryov Y.A.;
RT "Structure of alpha-latrotoxin oligomers reveals that divalent cation-
RT dependent tetramers form membrane pores.";
RL Nat. Struct. Biol. 7:48-53(2000).
CC -!- FUNCTION: Presynaptic neurotoxin that causes massive release of
CC neurotransmitters from vertebrate (but not invertebrate) nerve
CC terminals and endocrine cells via a complex mechanism involving
CC activation of receptor(s) and toxin insertion into the plasma membrane
CC with subsequent pore formation. Binds to neurexin-1-alpha (NRXN1) in a
CC calcium dependent manner, adhesion G protein-coupled receptor L1
CC (ADGRL1, also termed latrophilin-1 and calcium-independent receptor of
CC latrotoxin (CIRL)), and receptor-type tyrosine-protein phosphatase S
CC (PTPRS), also termed PTP sigma (PubMed:7592578, PubMed:8798521,
CC PubMed:12110683). NRXN1 and PTPRS are suggested to provide a platform
CC for binding and subsequent pore formation events (PubMed:9799228,
CC PubMed:11572875). In contrast, binding to ADGRL1 does not involve
CC oligomerization and channel formation, but direct downstream
CC stimulation of the synaptic fusion machinery (PubMed:12764091).
CC {ECO:0000269|PubMed:11572875, ECO:0000269|PubMed:12110683,
CC ECO:0000269|PubMed:12764091, ECO:0000269|PubMed:7592578,
CC ECO:0000269|PubMed:8798521, ECO:0000269|PubMed:9799228}.
CC -!- SUBUNIT: Homotetramer in membranes. {ECO:0000269|PubMed:10625427,
CC ECO:0000269|PubMed:10865132, ECO:0000269|PubMed:11572875}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:1888339,
CC ECO:0000269|PubMed:9792186}. Target cell membrane
CC {ECO:0000269|PubMed:10625427, ECO:0000269|PubMed:10865132}. Note=Forms
CC a membrane channel in the prey. {ECO:0000269|PubMed:10625427,
CC ECO:0000269|PubMed:10865132}.
CC -!- TISSUE SPECIFICITY: Expressed in venom gland, cephalothorax, and
CC abdomen tissues from both males and females.
CC {ECO:0000250|UniProtKB:P0DJE4}.
CC -!- DEVELOPMENTAL STAGE: Expressed in all life stages examined, including
CC adults, spiderlings and eggs. {ECO:0000250|UniProtKB:P0DJE4}.
CC -!- DOMAIN: The H8 helix is predicted to insert into membranes and form
CC pores by assembling into tetramers. The helix is contained within a
CC helical bundle domain that undergoes significant conformational changes
CC during pore formation to allow exposure of the H8 transmembrane helix
CC and transition of the toxin from a soluble monomer to a transmembrane
CC tetramer. {ECO:0000250|UniProtKB:Q9XZC0}.
CC -!- PTM: Processed by furin-like proteases at both the N- and C-termini.
CC -!- TOXIC DOSE: LD(50)is 20 ug/kg by subcutaneous injection into mice.
CC {ECO:0000269|PubMed:9792186}.
CC -!- BIOTECHNOLOGY: Is an essentiel tool for stimulating exocytosis and
CC study its mechanisms. Its mutant LTXN4C, which is unable to insert into
CC membranes and form pores, plays a key role in understanding the dual
CC mode of action of the wild-type toxin. {ECO:0000305|PubMed:19682210}.
CC -!- BIOTECHNOLOGY: May be used to antagonize botulinum neurotoxin poisoning
CC and attenuate the neuromuscular paralysis via synapse remodeling.
CC {ECO:0000305|PubMed:22069721}.
CC -!- MISCELLANEOUS: Is the main neurotoxin responsible for the human
CC envenomation syndrome known as latrodectism that results from bites by
CC Latrodectus species.
CC -!- MISCELLANEOUS: Anti-alpha-LTX monoclonal antibody 4C4.1 blocks
CC neurotransmitter release induced by this protein by preventing
CC tetramerization and ionophore activity once inserted into cell
CC membranes. However, 4C4.1 is incapable of reversing pore formation
CC (PubMed:11086220). {ECO:0000305|PubMed:11086220}.
CC -!- SIMILARITY: Belongs to the cationic peptide 01 (latrotoxin) family. 03
CC (alpha-latrotoxin) subfamily. {ECO:0000305}.
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DR EMBL; X55009; CAA38753.1; -; mRNA.
DR EMBL; AF069521; AAC78471.1; -; mRNA.
DR AlphaFoldDB; P23631; -.
DR SMR; P23631; -.
DR TCDB; 1.C.63.1.1; the Alpha-latrotoxin (latrotoxin) family.
DR ArachnoServer; AS000060; alpha-Latrotoxin-Lt1a.
DR PRO; PR:P23631; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR GO; GO:0006887; P:exocytosis; IEA:UniProtKB-KW.
DR Gene3D; 1.25.40.20; -; 5.
DR InterPro; IPR002110; Ankyrin_rpt.
DR InterPro; IPR036770; Ankyrin_rpt-contain_sf.
DR Pfam; PF12796; Ank_2; 5.
DR Pfam; PF13637; Ank_4; 3.
DR Pfam; PF13857; Ank_5; 1.
DR PRINTS; PR01415; ANKYRIN.
DR SMART; SM00248; ANK; 20.
DR SUPFAM; SSF48403; SSF48403; 3.
DR PROSITE; PS50297; ANK_REP_REGION; 1.
DR PROSITE; PS50088; ANK_REPEAT; 11.
PE 1: Evidence at protein level;
KW ANK repeat; Cleavage on pair of basic residues; Direct protein sequencing;
KW Disulfide bond; Exocytosis; G-protein coupled receptor impairing toxin;
KW Membrane; Neurotoxin; Presynaptic neurotoxin; Repeat; Secreted; Signal;
KW Target cell membrane; Target membrane; Toxin; Transmembrane.
FT SIGNAL 1..20
FT /evidence="ECO:0000269|PubMed:9792186"
FT CHAIN 21..1199
FT /note="Alpha-latrotoxin-Lt1a"
FT /id="PRO_0000001615"
FT PROPEP 1200..1401
FT /evidence="ECO:0000305"
FT /id="PRO_0000391352"
FT REPEAT 458..489
FT /note="ANK 1"
FT /evidence="ECO:0000255"
FT REPEAT 490..521
FT /note="ANK 2"
FT /evidence="ECO:0000255"
FT REPEAT 525..554
FT /note="ANK 3"
FT /evidence="ECO:0000255"
FT REPEAT 559..589
FT /note="ANK 4"
FT /evidence="ECO:0000255"
FT REPEAT 593..622
FT /note="ANK 5"
FT /evidence="ECO:0000255"
FT REPEAT 626..656
FT /note="ANK 6"
FT /evidence="ECO:0000255"
FT REPEAT 660..690
FT /note="ANK 7"
FT /evidence="ECO:0000255"
FT REPEAT 695..723
FT /note="ANK 8"
FT /evidence="ECO:0000255"
FT REPEAT 729..758
FT /note="ANK 9"
FT /evidence="ECO:0000255"
FT REPEAT 762..791
FT /note="ANK 10"
FT /evidence="ECO:0000255"
FT REPEAT 795..824
FT /note="ANK 11"
FT /evidence="ECO:0000255"
FT REPEAT 828..857
FT /note="ANK 12"
FT /evidence="ECO:0000255"
FT REPEAT 862..891
FT /note="ANK 13"
FT /evidence="ECO:0000255"
FT REPEAT 895..924
FT /note="ANK 14"
FT /evidence="ECO:0000255"
FT REPEAT 928..957
FT /note="ANK 15"
FT /evidence="ECO:0000255"
FT REPEAT 971..1003
FT /note="ANK 16"
FT /evidence="ECO:0000255"
FT REPEAT 1004..1033
FT /note="ANK 17"
FT /evidence="ECO:0000255"
FT REPEAT 1035..1064
FT /note="ANK 18"
FT /evidence="ECO:0000255"
FT REPEAT 1068..1097
FT /note="ANK 19"
FT /evidence="ECO:0000255"
FT REPEAT 1101..1131
FT /note="ANK 20"
FT /evidence="ECO:0000255"
FT REPEAT 1137..1166
FT /note="ANK 21"
FT /evidence="ECO:0000255"
FT REPEAT 1170..1199
FT /note="ANK 22"
FT /evidence="ECO:0000255"
FT REGION 17..20
FT /note="Furin-like endopeptidase recognition region"
FT REGION 238..257
FT /note="Helix H8 is the probable transmembrane region of the
FT tetrameric pore inserted in the target cell membrane"
FT /evidence="ECO:0000250|UniProtKB:Q9XZC0"
FT REGION 1026..1032
FT /note="4C4.1 epitope"
FT REGION 1196..1199
FT /note="Furin-like endopeptidase recognition region"
FT DISULFID 413..1066
FT /evidence="ECO:0000305|PubMed:10625427"
FT MUTAGEN 34
FT /note="C->S: Loss of function."
FT /evidence="ECO:0000269|PubMed:9799228"
FT MUTAGEN 91
FT /note="C->S: Loss of function."
FT /evidence="ECO:0000269|PubMed:9799228"
FT MUTAGEN 413
FT /note="C->S: Loss of function."
FT /evidence="ECO:0000269|PubMed:9799228"
FT MUTAGEN 448
FT /note="L->LVPRG: Loss of function (loss the ability of
FT pore-formation), but retains the full binding affinity to
FT receptors (mutant LTXN4C)."
FT /evidence="ECO:0000269|PubMed:9799228"
FT CONFLICT 60
FT /note="A -> V (in Ref. 2; AAC78471)"
FT /evidence="ECO:0000305"
FT CONFLICT 148
FT /note="E -> K (in Ref. 2; AAC78471)"
FT /evidence="ECO:0000305"
FT CONFLICT 162
FT /note="I -> V (in Ref. 2; AAC78471)"
FT /evidence="ECO:0000305"
FT CONFLICT 201
FT /note="F -> L (in Ref. 2; AAC78471)"
FT /evidence="ECO:0000305"
FT CONFLICT 467
FT /note="S -> A (in Ref. 2; AAC78471)"
FT /evidence="ECO:0000305"
FT CONFLICT 690
FT /note="V -> L (in Ref. 2; AAC78471)"
FT /evidence="ECO:0000305"
FT CONFLICT 783
FT /note="L -> I (in Ref. 2; AAC78471)"
FT /evidence="ECO:0000305"
FT CONFLICT 879
FT /note="I -> V (in Ref. 2; AAC78471)"
FT /evidence="ECO:0000305"
FT CONFLICT 1116
FT /note="H -> D (in Ref. 2; AAC78471)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1401 AA; 156857 MW; B38A22083C142A98 CRC64;
MISVGEIMER ANHSLVRMRR EGEDLTLEEK AEICSELELQ QKYVDIASNI IGDLSSLPIA
GKIAGTIAAA AMTATHVASG RLDIEQTLLG CSDLPFDQIK EVLENRFNEI DRKLDSHSAA
LEEITKLVEK SISVVEKTRK QMNKRFDEVM KSIQDAKVSP IISKINNFAR YFDTEKERIR
GLKLNDYILK LEEPNGILLH FKESRTPTDD SLQAPLFSII EEGYAVPKSI DDELAFKVLY
ALLYGTQTYV SVMFFLLEQY SFLANHYYEK GYLEKYDEYF NSLNNVFLDF KSSLVGTGTS
NNEGLLDRVL QVLMTVKNSE FLGLEKNGVD EMLNEKINLF NKIKEEIEGK QKMTLSETPE
NFAQISFDKD ITTPIGDWRD GREVRYAVQY ASETLFSKIS HWSDPVSVRE KACPTLRMPV
DQTRRNVLVF RKFDSSKPQL VGEITPYLSN FIDIDRDLYN AASNPDSAVG FKEFTKLNYD
GANIRATFDH GRTVFHAAAK SGNDKIMFGL TFLAKSTELN QPDKKGYTPI HVAADSGNAG
IVNLLIQRGV SINSKTYHFL QTPLHLAAQR GFVTTFQRLM ESPEININER DKDGFTPLHY
AIRGGERILE AFLNQISIDV NAKSNTGLTP FHLAIIKNDW PVASTLLGSK KVDINAVDEN
NITALHYAAI LGYLETTKQL INLKEINANV VSSPGLLSAL HYAILYKHDD VASFLMRSSN
VNVNLKALGG ITPLHLAVIQ GRKQILSLMF DIGVNIEQKT DEKYTPLHLA AMSKYPELIQ
ILLDQGSNFE AKTNSGATPL HLATFKGKSQ AALILLNNEV NWRDTDENGQ MPIHGAAMTG
LLDVAQAIIS IDATVVDIED KNSDTPLNLA AQNSHIDVIK YFIDQGADIN TRNKKGLAPL
LAFSKKGNLD MVKYLFDKNA NVYIADNDGM NFFYYAVQNG HLNIVKYAMS EKDKFEWSNT
DNNRRDECPN EECAISHFAV CDAVQFDRIE IVKYFVGTLG NFAICGPLHQ AARYGHLDIV
KYLVEEEFLS VDGSKTDTPL CYASENGHFT VVQYLVSNGA KVNHDCGNGM TAIDKAITKN
HLQVVQFLAA NGVDFRRKNS RGTTPFLTAV AENALHIAEY LIREKRQDIN INEQNVDKDT
ALHLAVYYKN LQMIKLLIKY GIDVTIRNAY DKTALDIAID AKFSNIVEYL KTKSGKFRRE
YKSSYGERSL LQTNQISNFI DRKNIEHDHP LFINADNESS ELFSKTASNI DVIGTLLLID
VLIRYFSKQG YISKESDSAS DGITQAAALS ITEKFEDVLN SLHNESAKEQ VDLAEVHGKV
YAALKSGRNS QIHQILCSSL NSISTLKPED MEKLESVIMN SHSSVSLPEV TDSANEAYGE
TLHLFGESCL HSDGILTKKL M
