MEL_APIME
ID MEL_APIME Reviewed; 70 AA.
AC P01501; I1VC84; P01503;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 21-JUL-1986, sequence version 1.
DT 25-MAY-2022, entry version 151.
DE RecName: Full=Melittin {ECO:0000303|PubMed:5592400};
DE Short=MEL;
DE Short=MLT;
DE AltName: Full=Allergen Api m 3 {ECO:0000305};
DE AltName: Full=Allergen Api m III {ECO:0000305};
DE AltName: Allergen=Api m 4 {ECO:0000305};
DE Flags: Precursor;
GN Name=MELT;
OS Apis mellifera (Honeybee).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; Pterygota;
OC Neoptera; Endopterygota; Hymenoptera; Apocrita; Aculeata; Apoidea; Apidae;
OC Apis.
OX NCBI_TaxID=7460;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=6309516; DOI=10.1111/j.1432-1033.1983.tb07626.x;
RA Vlasak R., Unger-Ullmann C., Kreil G., Frischauf A.-M.;
RT "Nucleotide sequence of cloned cDNA coding for honeybee prepromelittin.";
RL Eur. J. Biochem. 135:123-126(1983).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Hou C.-S., Guo L.-Q., Wang J.-R., You L.-F., Lin J.-F., Wu W.-H.,
RA Wang C.-S., Wang T.;
RL Submitted (APR-2012) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP PROTEIN SEQUENCE OF 44-69 (MELITTIN AND MELITTIN-2), AMIDATION AT GLN-69,
RP AND SUBCELLULAR LOCATION.
RX PubMed=5592400;
RA Habermann E., Jentsch J.;
RT "Sequence analysis of melittin from tryptic and peptic degradation
RT products.";
RL Hoppe-Seyler's Z. Physiol. Chem. 348:37-50(1967).
RN [4]
RP PROTEIN SEQUENCE OF 44-69 (MELITTIN-S), FUNCTION, IDENTIFICATION BY MASS
RP SPECTROMETRY, SEASONAL VARIATION, 3D-STRUCTURE MODELING, AND SUBCELLULAR
RP LOCATION.
RC STRAIN=Africanized honey bee; TISSUE=Venom;
RX PubMed=20472009; DOI=10.1016/j.peptides.2010.05.001;
RA Sciani J.M., Marques-Porto R., Lourenco A. Jr., Orsi R.D., Junior R.S.,
RA Barraviera B., Pimenta D.C.;
RT "Identification of a novel melittin isoform from Africanized Apis mellifera
RT venom.";
RL Peptides 31:1473-1479(2010).
RN [5]
RP PROTEIN SEQUENCE OF 44-69 (MELITTIN), IDENTIFICATION BY MASS SPECTROMETRY,
RP SEASONAL VARIATION, AND SUBCELLULAR LOCATION.
RC STRAIN=Africanized honey bee; TISSUE=Venom;
RX PubMed=20403370; DOI=10.1016/j.toxicon.2010.03.023;
RA Ferreira Junior R.S., Sciani J.M., Marques-Porto R., Junior A.L.,
RA Orsi R.D., Barraviera B., Pimenta D.C.;
RT "Africanized honey bee (Apis mellifera) venom profiling: Seasonal variation
RT of melittin and phospholipase A(2) levels.";
RL Toxicon 56:355-362(2010).
RN [6]
RP FUNCTION ON PHOSPHOLIPASE A2.
RX PubMed=4371280; DOI=10.1016/0014-5793(74)80354-6;
RA Mollay C., Kreil G.;
RT "Enhancement of bee venom phospholipase A2 activity by melittin, direct
RT lytic factor from cobra venom and polymyxin B.";
RL FEBS Lett. 46:141-144(1974).
RN [7]
RP FUNCTION.
RX PubMed=5794226; DOI=10.1016/s0021-9258(18)83408-1;
RA Sessa G., Freer J.H., Colacicco G., Weissmann G.;
RT "Interaction of a lytic polypeptide, melittin, with lipid membrane
RT systems.";
RL J. Biol. Chem. 244:3575-3582(1969).
RN [8]
RP SYNTHESIS OF 44-69 (MELITTIN AND MELITTIN-2), FUNCTION, AND MUTAGENESIS OF
RP 44-GLY--PRO-57.
RX PubMed=5139482; DOI=10.1007/bf02136851;
RA Schroeder E., Luebke K., Lehmann M., Beetz I.;
RT "Haemolytic activity and action on the surface tension of aqueous solutions
RT of synthetic melittins and their derivatives.";
RL Experientia 27:764-765(1971).
RN [9]
RP SYNTHESIS OF 44-69, AND FORMYLATION AT GLY-44.
RX PubMed=5139483; DOI=10.1007/bf02136852;
RA Luebke K., Matthes S., Kloss G.;
RT "Isolation and structure of N 1-formyl melittin.";
RL Experientia 27:765-767(1971).
RN [10]
RP ALLERGEN.
RX PubMed=850023; DOI=10.1016/0091-6749(77)90056-2;
RA Paull B.R., Yunginger J.W., Gleich G.J.;
RT "Melittin: an allergen of honeybee venom.";
RL J. Allergy Clin. Immunol. 59:334-338(1977).
RN [11]
RP SUBUNIT.
RX PubMed=456586; DOI=10.1016/0014-5793(79)80956-4;
RA Faucon J.F., Dufourcq J., Lussan C.;
RT "The self-association of melittin and its binding to lipids: an intrinsic
RT fluorescence polarization study.";
RL FEBS Lett. 102:187-190(1979).
RN [12]
RP SUBUNIT.
RX PubMed=7378451; DOI=10.1016/0005-2795(80)90033-1;
RA Lauterwein J., Brown L.R., Wuethrich K.;
RT "High-resolution 1H-NMR studies of monomeric melittin in aqueous
RT solution.";
RL Biochim. Biophys. Acta 622:219-230(1980).
RN [13]
RP FUNCTION, AND SUBUNIT.
RX PubMed=6269667; DOI=10.1016/s0006-3495(81)84719-4;
RA Tosteson M.T., Tosteson D.C.;
RT "The sting. Melittin forms channels in lipid bilayers.";
RL Biophys. J. 36:109-116(1981).
RN [14]
RP FUNCTION.
RX PubMed=7061434; DOI=10.1016/s0021-9258(18)34947-0;
RA Kempf C., Klausner R.D., Weinstein J.N., Van Renswoude J., Pincus M.,
RA Blumenthal R.;
RT "Voltage-dependent trans-bilayer orientation of melittin.";
RL J. Biol. Chem. 257:2469-2476(1982).
RN [15]
RP SUBUNIT, AND FUNCTION AS MONOMER.
RX PubMed=6830776; DOI=10.1016/0005-2736(83)90473-x;
RA Hider R.C., Khader F., Tatham A.S.;
RT "Lytic activity of monomeric and oligomeric melittin.";
RL Biochim. Biophys. Acta 728:206-214(1983).
RN [16]
RP FUNCTION.
RX PubMed=4057243; DOI=10.1007/bf01870697;
RA Tosteson M.T., Holmes S.J., Razin M., Tosteson D.C.;
RT "Melittin lysis of red cells.";
RL J. Membr. Biol. 87:35-44(1985).
RN [17]
RP FUNCTION.
RX PubMed=3443079; DOI=10.1007/bf00263679;
RA Talbot J.C., Faucon J.F., Dufourcq J.;
RT "Different states of self-association of melittin in phospholipid bilayers.
RT A resonance energy transfer approach.";
RL Eur. Biophys. J. 15:147-157(1987).
RN [18]
RP FUNCTION.
RX PubMed=3666135; DOI=10.1016/0014-5793(87)80526-4;
RA Batenburg A.M., van Esch J.H., Leunissen-Bijvelt J., Verkleij A.J.,
RA de Kruijff B.;
RT "Interaction of melittin with negatively charged phospholipids:
RT consequences for lipid organization.";
RL FEBS Lett. 223:148-154(1987).
RN [19]
RP TOXIC DOSE.
RX PubMed=10669014; DOI=10.1016/s0041-0101(99)00136-1;
RA Shiomi K., Igarashi T., Yokota H., Nagashima Y., Ishida M.;
RT "Isolation and structures of grammistins, peptide toxins from the skin
RT secretion of the soapfish Grammistes sexlineatus.";
RL Toxicon 38:91-103(2000).
RN [20]
RP SUBUNIT.
RX PubMed=11509361; DOI=10.1016/s0006-3495(01)75802-x;
RA Yang L., Harroun T.A., Weiss T.M., Ding L., Huang H.W.;
RT "Barrel-stave model or toroidal model? A case study on melittin pores.";
RL Biophys. J. 81:1475-1485(2001).
RN [21]
RP SYNTHESIS OF 44-69, AND FUNCTION.
RX PubMed=24512991; DOI=10.1016/j.peptides.2014.01.026;
RA Park D., Jung J.W., Lee M.O., Lee S.Y., Kim B., Jin H.J., Kim J., Ahn Y.J.,
RA Lee K.W., Song Y.S., Hong S., Womack J.E., Kwon H.W.;
RT "Functional characterization of naturally occurring melittin peptide
RT isoforms in two honey bee species, Apis mellifera and Apis cerana.";
RL Peptides 53:185-193(2014).
RN [22]
RP SYNTHESIS, AND MUTAGENESIS OF THR-53 AND 65-ARG--GLN-69.
RX PubMed=28720433; DOI=10.1016/j.bbamem.2017.07.005;
RA Fennouri A., Mayer S.F., Schroeder T.B.H., Mayer M.;
RT "Single channel planar lipid bilayer recordings of the melittin variant
RT MelP5.";
RL Biochim. Biophys. Acta 1859:2051-2057(2017).
RN [23]
RP REVIEW.
RX PubMed=2187536; DOI=10.1016/0304-4157(90)90006-x;
RA Dempsey C.E.;
RT "The actions of melittin on membranes.";
RL Biochim. Biophys. Acta 1031:143-161(1990).
RN [24]
RP REVIEW, AND FUNCTION AS A PAIN PRODUCING SUBSTANCE.
RX PubMed=26983715; DOI=10.1007/s12264-016-0024-y;
RA Chen J., Guan S.M., Sun W., Fu H.;
RT "Melittin, the major pain-producing substance of bee venom.";
RL Neurosci. Bull. 32:265-272(2016).
RN [25]
RP REVIEW, AND PHARMACEUTICAL.
RX PubMed=28536009; DOI=10.1016/j.canlet.2017.05.010;
RA Rady I., Siddiqui I.A., Rady M., Mukhtar H.;
RT "Melittin, a major peptide component of bee venom, and its conjugates in
RT cancer therapy.";
RL Cancer Lett. 402:16-31(2017).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 44-69.
RX PubMed=7076662; DOI=10.1016/s0021-9258(20)65098-0;
RA Terwilliger T.C., Eisenberg D.;
RT "The structure of melittin. II. Interpretation of the structure.";
RL J. Biol. Chem. 257:6016-6022(1982).
RN [27]
RP STRUCTURE BY NMR OF 44-69.
RA Barnham K.J., Hewish D., Werkmeister J., Curtain C., Kirkpatrick A.,
RA Bartone N., Norton R., Rivett D.;
RL Submitted (JUN-1998) to the PDB data bank.
CC -!- FUNCTION: Melittin: Main toxin of bee venom with strong hemolytic
CC activity and antimicrobial activity (PubMed:5794226, PubMed:5139482,
CC PubMed:4057243, PubMed:24512991). It has enhancing effects on bee venom
CC phospholipase A2 activity (PubMed:4371280). This amphipathic toxin
CC binds to negatively charged membrane surface and forms pore by
CC inserting into lipid bilayers inducing the leakage of ions and
CC molecules and the enhancement of permeability that ultimately leads to
CC cell lysis (PubMed:6830776, PubMed:4057243, PubMed:3666135). It acts as
CC a voltage-gated pore with higher selectivity for anions over cations
CC (PubMed:6269667). The ion conductance has been shown to be voltage-
CC dependent (PubMed:7061434). Self-association of melittin in membranes
CC is promoted by high ionic strength, but not by the presence of
CC negatively charged lipids (PubMed:3443079). In vivo, intradermal
CC injection into healthy human volunteers produce sharp pain sensation
CC and an inflammatory response (PubMed:26983715). It produces pain by
CC activating primary nociceptor cells directly and indirectly due to its
CC ability to activate plasma membrane phospholipase A2 and its pore-
CC forming activity (PubMed:26983715). {ECO:0000269|PubMed:24512991,
CC ECO:0000269|PubMed:26983715, ECO:0000269|PubMed:3443079,
CC ECO:0000269|PubMed:3666135, ECO:0000269|PubMed:4057243,
CC ECO:0000269|PubMed:4371280, ECO:0000269|PubMed:5139482,
CC ECO:0000269|PubMed:5794226, ECO:0000269|PubMed:6269667,
CC ECO:0000269|PubMed:6830776, ECO:0000269|PubMed:7061434}.
CC -!- FUNCTION: Melittin-S: 1.4-fold less hemolytic and adopts a less
CC organized secondary structure than melittin.
CC {ECO:0000269|PubMed:20472009}.
CC -!- FUNCTION: Melittin-2: Has strong hemolytic activity (PubMed:5139482).
CC {ECO:0000305|PubMed:5139482}.
CC -!- SUBUNIT: Monomer (in solution and for integration into membranes),
CC homotetramer (in solution and potentially as a toroidal pore in
CC membranes), and potenially homomultimer (as a toroidal pore in
CC membranes). {ECO:0000269|PubMed:11509361, ECO:0000269|PubMed:456586,
CC ECO:0000269|PubMed:6269667, ECO:0000269|PubMed:6830776,
CC ECO:0000269|PubMed:7378451}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:20403370,
CC ECO:0000269|PubMed:20472009, ECO:0000269|PubMed:5592400}. Target cell
CC membrane {ECO:0000269|PubMed:11509361, ECO:0000269|PubMed:456586,
CC ECO:0000269|PubMed:6269667}. Note=Alpha-helical peptides form toroidal
CC pores in the prey. {ECO:0000269|PubMed:11509361,
CC ECO:0000269|PubMed:20403370, ECO:0000269|PubMed:20472009,
CC ECO:0000269|PubMed:456586, ECO:0000269|PubMed:5592400,
CC ECO:0000269|PubMed:6269667}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland. {ECO:0000305}.
CC -!- ALLERGEN: Causes an allergic reaction in human.
CC {ECO:0000269|PubMed:850023}.
CC -!- TOXIC DOSE: LD(50) is 2.7 ug/ml against killifish.
CC -!- PHARMACEUTICAL: Melittin is an attractive candidate for cancer
CC chemotherapy causing more damage to the tumor cell membranes since its
CC membrane potential is higher and cells are less likely to develop
CC resistance to a membrane pore formation. Despite this potential
CC applicability of melittin, its rapid degradation in the blood and its
CC non-specific cellular lytic activity -including hemolysis- poses
CC significant challenges. However, melittin and/or its conjugates can
CC work in conjunction with hormone receptors, gene therapy or as
CC nanoparticles for targeted therapies of some cancer types.
CC {ECO:0000305|PubMed:28536009}.
CC -!- MISCELLANEOUS: N-formyl-melittin major has 80% of the activity of
CC melittin. {ECO:0000269|PubMed:5139483}.
CC -!- MISCELLANEOUS: Melittin: The secretion of this protein into venom
CC follows a seasonal pattern. This variation is synchronized with
CC phospholipase A2 variation, i.e. their production increase in the same
CC months. {ECO:0000269|PubMed:20403370}.
CC -!- MISCELLANEOUS: Melittin-S: The secretion of this protein into venom
CC follows a seasonal pattern, the maximum secretion occurring during the
CC (southern) winter months. {ECO:0000269|PubMed:20472009}.
CC -!- MISCELLANEOUS: Exists in two forms, due to cis-trans isomerization at
CC 56-Leu-Pro-57. The trans conformation is the major form. The trans
CC conformation is required for an alpha-helix.
CC {ECO:0000269|PubMed:7378451}.
CC -!- MISCELLANEOUS: The derivative MelP5 is amidated.
CC {ECO:0000305|PubMed:28720433}.
CC -!- SIMILARITY: Belongs to the melittin family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Why Pooh luvvs hunny - Issue
CC 12 of July 2001;
CC URL="https://web.expasy.org/spotlight/back_issues/012";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Melittin entry;
CC URL="https://en.wikipedia.org/wiki/Melittin";
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DR EMBL; X02007; CAA26038.1; -; mRNA.
DR EMBL; JQ900378; AFI40556.1; -; mRNA.
DR PIR; A91133; MPHB1.
DR RefSeq; NP_001011607.1; NM_001011607.1.
DR PDB; 1BH1; NMR; -; A=44-69.
DR PDB; 2MLT; X-ray; 2.00 A; A/B=44-69.
DR PDB; 2MW6; NMR; -; A=44-69.
DR PDB; 3QRX; X-ray; 2.20 A; B=44-69.
DR PDB; 6DST; NMR; -; A=44-69.
DR PDB; 6O4M; X-ray; 1.27 A; A/B/C/D=44-69.
DR PDBsum; 1BH1; -.
DR PDBsum; 2MLT; -.
DR PDBsum; 2MW6; -.
DR PDBsum; 3QRX; -.
DR PDBsum; 6DST; -.
DR PDBsum; 6O4M; -.
DR AlphaFoldDB; P01501; -.
DR BMRB; P01501; -.
DR SMR; P01501; -.
DR BioGRID; 1455502; 1.
DR DIP; DIP-48928N; -.
DR STRING; 7460.GB44112-PA; -.
DR ChEMBL; CHEMBL3351188; -.
DR Allergome; 3091; Api m 4.0101.
DR Allergome; 48; Api m 4.
DR TCDB; 1.C.18.1.1; the melittin (melittin) family.
DR PaxDb; P01501; -.
DR EnsemblMetazoa; NM_001011607; NP_001011607; GeneID_406130.
DR GeneID; 406130; -.
DR KEGG; ame:406130; -.
DR CTD; 38785; -.
DR HOGENOM; CLU_2759907_0_0_1; -.
DR EvolutionaryTrace; P01501; -.
DR Proteomes; UP000005203; Unplaced.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0046930; C:pore complex; IEA:UniProtKB-KW.
DR GO; GO:0015288; F:porin activity; IEA:UniProtKB-KW.
DR GO; GO:0004860; F:protein kinase inhibitor activity; IEA:InterPro.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR GO; GO:0044179; P:hemolysis in another organism; IEA:UniProtKB-KW.
DR GO; GO:0006811; P:ion transport; IEA:UniProtKB-KW.
DR DisProt; DP02951; -.
DR InterPro; IPR002116; Melittin/Api_allergen.
DR Pfam; PF01372; Melittin; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Allergen; Amidation; Antimicrobial; Cytolysis;
KW Direct protein sequencing; Formylation; Hemolysis; Ion transport; Membrane;
KW Pharmaceutical; Porin; Reference proteome; Secreted; Signal;
KW Target cell membrane; Target membrane; Toxin; Transmembrane; Transport.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT PROPEP 22..43
FT /note="Removed by a dipeptidylpeptidase"
FT /evidence="ECO:0000305|PubMed:20403370,
FT ECO:0000305|PubMed:20472009, ECO:0000305|PubMed:5592400"
FT /id="PRO_0000035148"
FT PEPTIDE 44..69
FT /note="Melittin"
FT /evidence="ECO:0000269|PubMed:20403370,
FT ECO:0000269|PubMed:20472009, ECO:0000269|PubMed:5592400"
FT /id="PRO_0000035149"
FT SITE 57
FT /note="Important for the flexibility at the center of the
FT helix, flexibility that is important for the stability of
FT the voltage-gated pore"
FT /evidence="ECO:0000269|PubMed:2187536"
FT MOD_RES 44
FT /note="N-formylglycine; partial"
FT /evidence="ECO:0000269|PubMed:5139483"
FT MOD_RES 69
FT /note="Glutamine amide"
FT /evidence="ECO:0000269|PubMed:5592400"
FT VARIANT 53
FT /note="T -> S (in melittin-S)"
FT VARIANT 64
FT /note="K -> S (in melittin-2; possibly an artifact)"
FT VARIANT 66
FT /note="K -> KK (in melittin-2; possibly an artifact)"
FT MUTAGEN 44..57
FT /note="Missing: Very important decrease of hemolytic
FT activity and capacity of lowering the surface tension of
FT aqueous solutions."
FT /evidence="ECO:0000269|PubMed:5139482"
FT MUTAGEN 53
FT /note="T->A: In MelP5; increase in size of pores (10-12
FT monomers) that form at lower concentrations of the toxin."
FT /evidence="ECO:0000269|PubMed:28720433"
FT MUTAGEN 57
FT /note="P->A: Loss of flexibility in the center of the
FT helix, is twice as effective as melittin as a hemolytic
FT agent but has very poor voltage-gated pore activity in
FT planar bilayers and voltage-dependent ion conductionce is
FT supported only at very high ionic strengths."
FT /evidence="ECO:0000269|PubMed:2187536"
FT MUTAGEN 65..69
FT /note="RKRQQ->AAQQL: In MelP5; increase in size of pores
FT (10-12 monomers) that form at lower concentrations of the
FT toxin."
FT /evidence="ECO:0000269|PubMed:28720433"
FT HELIX 45..54
FT /evidence="ECO:0007829|PDB:6O4M"
FT HELIX 56..61
FT /evidence="ECO:0007829|PDB:6O4M"
FT HELIX 64..68
FT /evidence="ECO:0007829|PDB:6O4M"
SQ SEQUENCE 70 AA; 7585 MW; 607F52C091C23BB6 CRC64;
MKFLVNVALV FMVVYISYIY AAPEPEPAPE PEAEADAEAD PEAGIGAVLK VLTTGLPALI
SWIKRKRQQG
