VM2EA_ECHCS
ID VM2EA_ECHCS Reviewed; 186 AA.
AC P17347; E9JGG9;
DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
DT 25-MAY-2022, sequence version 3.
DT 03-AUG-2022, entry version 117.
DE RecName: Full=Disintegrin metalloproteinase/disintegrin echistatin;
DE Contains:
DE RecName: Full=Snake venom metalloproteinase {ECO:0000305};
DE Short=SVMP {ECO:0000305};
DE EC=3.4.24.- {ECO:0000305};
DE Contains:
DE RecName: Full=Disintegrin echistatin {ECO:0000303|PubMed:33182321};
DE Short=Ech {ECO:0000303|PubMed:33182321};
DE AltName: Full=Carinatin;
DE AltName: Full=Disintegrin echistatin-alpha-1 {ECO:0000303|PubMed:2320569};
DE AltName: Full=Platelet aggregation activation inhibitor;
DE Contains:
DE RecName: Full=Disintegrin echistatin-alpha-2 {ECO:0000303|PubMed:2320569};
DE Flags: Precursor; Fragment;
OS Echis carinatus sochureki (Saw-scaled viper).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Lepidosauria; Squamata; Bifurcata; Unidentata; Episquamata; Toxicofera;
OC Serpentes; Colubroidea; Viperidae; Viperinae; Echis.
OX NCBI_TaxID=124223;
RN [1] {ECO:0000312|EMBL:ADI47720.1}
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Venom gland;
RX PubMed=21062752; DOI=10.1093/molbev/msq302;
RA Casewell N.R., Wagstaff S.C., Harrison R.A., Wuster W.;
RT "Gene tree parsimony of multilocus snake venom protein families reveals
RT species tree conflict as a result of multiple parallel gene loss.";
RL Mol. Biol. Evol. 28:1157-1172(2011).
RN [2]
RP PROTEIN SEQUENCE OF 131-179, FUNCTION, SUBUNIT, AND SUBCELLULAR LOCATION.
RC TISSUE=Venom;
RX PubMed=3198653; DOI=10.1016/s0021-9258(19)77710-2;
RA Gan Z.R., Gould R.J., Jacobs J.W., Friedman P.A., Polokoff M.A.;
RT "Echistatin. A potent platelet aggregation inhibitor from the venom of the
RT viper, Echis carinatus.";
RL J. Biol. Chem. 263:19827-19832(1988).
RN [3]
RP PROTEIN SEQUENCE OF 131-179, PYROGLUTAMATE FORMATION AT GLN-131 (FORM
RP ALPHA2) FUNCTION, AND SUBCELLULAR LOCATION.
RC TISSUE=Venom;
RX PubMed=2320569; DOI=10.1073/pnas.87.7.2471;
RA Dennis M.S., Henzel W.J., Pitti R.M., Lipari M.T., Napier M.A.,
RA Deisher T.A., Bunting S., Lazarus R.A.;
RT "Platelet glycoprotein IIb-IIIa protein antagonists from snake venoms:
RT evidence for a family of platelet-aggregation inhibitors.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:2471-2475(1990).
RN [4]
RP DISULFIDE BONDS.
RX PubMed=1516704; DOI=10.1016/0014-5793(92)80797-k;
RA Calvete J.J., Wang Y., Mann K., Schaefer W., Niewiarwoski S., Stewart G.J.;
RT "The disulfide bridge pattern of snake venom disintegrins, flavoridin and
RT echistatin.";
RL FEBS Lett. 309:316-320(1992).
RN [5]
RP FUNCTION, AND MUTAGENESIS OF ARG-154 AND ASP-157.
RX PubMed=9269775;
RA Marcinkiewicz C., Vijay-Kumar S., McLane M.A., Niewiarowski S.;
RT "Significance of RGD loop and C-terminal domain of echistatin for
RT recognition of alphaIIb beta3 and alpha(v) beta3 integrins and expression
RT of ligand-induced binding site.";
RL Blood 90:1565-1575(1997).
RN [6]
RP REVIEW.
RX PubMed=9923894; DOI=10.1016/s0140-6736(98)11086-3;
RA Topol E.J., Byzova T.V., Plow E.F.;
RT "Platelet GPIIb-IIIa blockers.";
RL Lancet 353:227-231(1999).
RN [7]
RP STRUCTURE BY NMR OF 131-179.
RX PubMed=1761035; DOI=10.1111/j.1432-1033.1991.tb16378.x;
RA Dalvit C., Widmer H., Bovermann G., Breckenridge R., Metternich R.;
RT "1H NMR studies of echistatin in solution. Sequential resonance assignments
RT and secondary structure.";
RL Eur. J. Biochem. 202:315-321(1991).
RN [8]
RP STRUCTURE BY NMR OF 131-179.
RX PubMed=1761036; DOI=10.1111/j.1432-1033.1991.tb16379.x;
RA Cooke R.M., Carter B.G., Martin D.M.A., Murray-Rust P., Weir M.P.;
RT "Nuclear magnetic resonance studies of the snake toxin echistatin. 1H
RT resonance assignments and secondary structure.";
RL Eur. J. Biochem. 202:323-328(1991).
RN [9]
RP STRUCTURE BY NMR OF 131-179, AND DISULFIDE BONDS (PARTIAL).
RX PubMed=1761037; DOI=10.1111/j.1432-1033.1991.tb16380.x;
RA Saudek V., Atkinson R.A., Lepage P., Pelton J.T.;
RT "The secondary structure of echistatin from 1H-NMR, circular-dichroism and
RT Raman spectroscopy.";
RL Eur. J. Biochem. 202:329-338(1991).
RN [10]
RP STRUCTURE BY NMR OF 131-179.
RX PubMed=1854743; DOI=10.1021/bi00244a003;
RA Saudek V., Atkinson R.A., Pelton J.T.;
RT "Three-dimensional structure of echistatin, the smallest active RGD
RT protein.";
RL Biochemistry 30:7369-7372(1991).
RN [11]
RP STRUCTURE BY NMR OF 131-179.
RX PubMed=1661142; DOI=10.1021/bi00114a004;
RA Chen Y., Pitzenberger S.M., Garsky V.M., Lumma P.K., Sanyal G., Baum J.;
RT "Proton NMR assignments and secondary structure of the snake venom protein
RT echistatin.";
RL Biochemistry 30:11625-11636(1991).
RN [12] {ECO:0007744|PDB:2ECH}
RP STRUCTURE BY NMR OF 132-179, AND DISULFIDE BONDS.
RX PubMed=7928087; DOI=10.1111/j.1399-3011.1994.tb00558.x;
RA Atkinson R.A., Saudek V., Pelton J.T.;
RT "Echistatin: the refined structure of a disintegrin in solution by 1H NMR
RT and restrained molecular dynamics.";
RL Int. J. Pept. Protein Res. 43:563-572(1994).
RN [13] {ECO:0007744|PDB:1RO3}
RP STRUCTURE BY NMR OF 132-179, AND DISULFIDE BONDS.
RX PubMed=15535803; DOI=10.1042/bj20041343;
RA Monleon D., Esteve V., Kovacs H., Calvete J.J., Celda B.;
RT "Conformation and concerted dynamics of the integrin-binding site and the
RT C-terminal region of echistatin revealed by homonuclear NMR.";
RL Biochem. J. 387:57-66(2005).
RN [14] {ECO:0007744|PDB:6LSQ}
RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 131-179, FUNCTION, DISULFIDE
RP BONDS, RECOMBINANT EXPRESSION, AND MUTAGENESIS OF PRO-173; HIS-174;
RP 174-HIS--THR-179 AND LYS-175.
RX PubMed=33182321; DOI=10.3390/toxins12110709;
RA Chen Y.C., Chang Y.T., Chen C.Y., Shiu J.H., Cheng C.H., Huang C.H.,
RA Chen J.F., Chuang W.J.;
RT "Structural insight into integrin recognition and anticancer activity of
RT echistatin.";
RL Toxins 12:0-0(2020).
CC -!- FUNCTION: [Snake venom metalloproteinase]: Impairs hemostasis in the
CC envenomed animal. {ECO:0000250|UniProtKB:Q5XUW8, ECO:0000305}.
CC -!- FUNCTION: [Disintegrin echistatin]: Potent inhibitor of ligand binding
CC to the integrins alpha-V/beta-3 (ITGAV/ITGB3) (IC(50)=20.7 nM), alpha-
CC IIb/beta-3 (ITGA2B/ITGB3) (IC(50)=51.5 nM), alpha-5/beta-1
CC (ITGA5/ITGB1) (IC(50)=132.6 nM), and moderate inhibitor of ligand
CC binding to the integrin alpha-V/beta-5 (ITGAV/ITGB5) (IC(50)=286.4 nM)
CC (PubMed:9269775, PubMed:33182321). Competition with fibrinogen for the
CC RGD recognition sites on the alpha-IIb/beta-3 integrin (glyco-protein
CC IIb/IIIa complex) results in the inhibition of platelet aggregation and
CC other antithrombotic properties such as an ability to prevent coronary
CC thrombosis in animal models (PubMed:3198653, PubMed:2320569)
CC (Probable). Is also a potent inhibitor of bone resorption. This results
CC from the blocking of the interaction of alpha-V/beta-3 integrin on the
CC surface of osteoclasts with bone extracellular matrix (Probable). In
CC addition, interaction with alpha-V/beta-3 also inhibits human umbilical
CC vein endothelial cells (HUVEC) proliferation (IC(50)=103.2 nM) and
CC inhibits the migration of some tumor cells (IC(50)=1.5-154.5 nM),
CC suggesting that this disintegrin could be a good scaffold to design
CC potent antiangiogenic agents by modifying its unique C-terminal tail
CC structure (Probable) (PubMed:33182321). {ECO:0000269|PubMed:2320569,
CC ECO:0000269|PubMed:3198653, ECO:0000269|PubMed:33182321,
CC ECO:0000269|PubMed:9269775, ECO:0000305|PubMed:9269775}.
CC -!- SUBUNIT: Monomer (disintegrin). {ECO:0000269|PubMed:3198653}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:2320569,
CC ECO:0000269|PubMed:3198653}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:2320569, ECO:0000305|PubMed:3198653}.
CC -!- MISCELLANEOUS: This peptide has served as a model to produce tirofiban
CC (Aggrastat), a nonpeptide drug available in the market as antiplatelet
CC agent. {ECO:0000305|PubMed:9923894}.
CC -!- MISCELLANEOUS: The disintegrin belongs to the short disintegrin
CC subfamily. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the venom metalloproteinase (M12B) family. P-II
CC subfamily. P-IIa sub-subfamily. {ECO:0000305}.
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DR EMBL; GU012266; ADI47720.1; -; mRNA.
DR PIR; A32029; A32029.
DR PIR; A35982; A35982.
DR PDB; 1RO3; NMR; -; A=131-179.
DR PDB; 2ECH; NMR; -; A=132-179.
DR PDB; 6LSQ; X-ray; 1.80 A; A/B=131-179.
DR PDBsum; 1RO3; -.
DR PDBsum; 2ECH; -.
DR PDBsum; 6LSQ; -.
DR AlphaFoldDB; P17347; -.
DR BMRB; P17347; -.
DR SMR; P17347; -.
DR MEROPS; M12.164; -.
DR EvolutionaryTrace; P17347; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0008237; F:metallopeptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR CDD; cd04269; ZnMc_adamalysin_II_like; 1.
DR Gene3D; 3.40.390.10; -; 1.
DR Gene3D; 4.10.70.10; -; 1.
DR InterPro; IPR018358; Disintegrin_CS.
DR InterPro; IPR001762; Disintegrin_dom.
DR InterPro; IPR036436; Disintegrin_dom_sf.
DR InterPro; IPR024079; MetalloPept_cat_dom_sf.
DR InterPro; IPR001590; Peptidase_M12B.
DR InterPro; IPR034027; Reprolysin_adamalysin.
DR Pfam; PF00200; Disintegrin; 1.
DR Pfam; PF01421; Reprolysin; 1.
DR PRINTS; PR00289; DISINTEGRIN.
DR SMART; SM00050; DISIN; 1.
DR SUPFAM; SSF57552; SSF57552; 1.
DR PROSITE; PS50215; ADAM_MEPRO; 1.
DR PROSITE; PS00427; DISINTEGRIN_1; 1.
DR PROSITE; PS50214; DISINTEGRIN_2; 1.
DR PROSITE; PS00142; ZINC_PROTEASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cell adhesion impairing toxin; Direct protein sequencing;
KW Disulfide bond; Hemostasis impairing toxin; Hydrolase; Metal-binding;
KW Metalloprotease; Platelet aggregation inhibiting toxin; Protease;
KW Pyrrolidone carboxylic acid; Secreted; Toxin; Zinc.
FT CHAIN <1..108
FT /note="Snake venom metalloproteinase"
FT /evidence="ECO:0000305"
FT /id="PRO_0000455531"
FT PROPEP 109..130
FT /evidence="ECO:0000305"
FT /id="PRO_0000455532"
FT CHAIN 131..179
FT /note="Disintegrin echistatin"
FT /evidence="ECO:0000269|PubMed:2320569,
FT ECO:0000269|PubMed:3198653"
FT /id="PRO_0000007242"
FT CHAIN 131..177
FT /note="Disintegrin echistatin-alpha-2"
FT /evidence="ECO:0000269|PubMed:2320569"
FT /id="PRO_0000007243"
FT PROPEP 180..186
FT /evidence="ECO:0000305"
FT /id="PRO_0000455533"
FT DOMAIN <1..95
FT /note="Peptidase M12B"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00276"
FT DOMAIN 103..177
FT /note="Disintegrin"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00068"
FT MOTIF 154..156
FT /note="Cell attachment site"
FT ACT_SITE 36
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00276"
FT BINDING 35
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00276"
FT BINDING 39
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00276"
FT BINDING 45
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00276"
FT MOD_RES 131
FT /note="Pyrrolidone carboxylic acid; in form alpha-2"
FT /evidence="ECO:0000269|PubMed:2320569"
FT DISULFID 10..90
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00276"
FT DISULFID 50..74
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00276"
FT DISULFID 52..57
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00276"
FT DISULFID 132..141
FT /evidence="ECO:0000269|PubMed:1516704,
FT ECO:0000269|PubMed:15535803, ECO:0000269|PubMed:1761037,
FT ECO:0000269|PubMed:33182321, ECO:0000269|PubMed:7928087,
FT ECO:0007744|PDB:1RO3, ECO:0007744|PDB:2ECH,
FT ECO:0007744|PDB:6LSQ"
FT DISULFID 137..162
FT /evidence="ECO:0000269|PubMed:1516704,
FT ECO:0000269|PubMed:15535803, ECO:0000269|PubMed:33182321,
FT ECO:0000269|PubMed:7928087, ECO:0007744|PDB:1RO3,
FT ECO:0007744|PDB:2ECH, ECO:0007744|PDB:6LSQ"
FT DISULFID 138..167
FT /evidence="ECO:0000269|PubMed:1516704,
FT ECO:0000269|PubMed:15535803, ECO:0000269|PubMed:33182321,
FT ECO:0000269|PubMed:7928087, ECO:0007744|PDB:1RO3,
FT ECO:0007744|PDB:2ECH, ECO:0007744|PDB:6LSQ"
FT DISULFID 150..169
FT /evidence="ECO:0000269|PubMed:1516704,
FT ECO:0000269|PubMed:15535803, ECO:0000269|PubMed:1761037,
FT ECO:0000269|PubMed:33182321, ECO:0000269|PubMed:7928087,
FT ECO:0007744|PDB:1RO3, ECO:0007744|PDB:2ECH,
FT ECO:0007744|PDB:6LSQ"
FT MUTAGEN 154
FT /note="R->A: Does not act on alpha-IIb/beta-3 and alpha-
FT V/beta-3."
FT /evidence="ECO:0000269|PubMed:9269775"
FT MUTAGEN 157
FT /note="D->W: Increase in binding to alpha-IIb/beta-3 and
FT decrease in binding to alpha-V/beta-3."
FT /evidence="ECO:0000269|PubMed:9269775"
FT MUTAGEN 173
FT /note="P->A: 2.2-fold decrease in inhibitory potency
FT towards a5b1, and no change towards avb3 and aiibb3."
FT /evidence="ECO:0000269|PubMed:33182321"
FT MUTAGEN 174..179
FT /note="Missing: Important (6-18-fold) decrease of
FT inhibitory potency towards integrins alpha-V/beta-3
FT (ITGAV/ITGB3), alpha-IIb/beta-3 (ITGA2B/ITGB3), alpha-
FT 5/beta-1 (ITGA5/ITGB1), and alpha-V/beta-5 (ITGAV/ITGB5)."
FT /evidence="ECO:0000269|PubMed:33182321"
FT MUTAGEN 174
FT /note="H->A: Increase in inhibitory potency towards aiibb3
FT (2.5-fold) and a5b1 (4.4-fold), and no change towards
FT avb3."
FT /evidence="ECO:0000269|PubMed:33182321"
FT MUTAGEN 175
FT /note="K->A: 2.6-fold decrease in inhibitory potency
FT towards aiibb3, 1.6-fold increase in inhibitory potency
FT towards a5b1, and no change towards avb3."
FT /evidence="ECO:0000269|PubMed:33182321"
FT MUTAGEN 175
FT /note="K->E: Between 4.8 to 10.4-fold decrease in
FT inhibiting the migration of tumor cells."
FT /evidence="ECO:0000269|PubMed:33182321"
FT CONFLICT 131
FT /note="Q -> E (in Ref. 2; AA sequence and 3; AA sequence)"
FT /evidence="ECO:0000305"
FT NON_TER 1
FT /evidence="ECO:0000305"
FT STRAND 8..13
FT /evidence="ECO:0007829|PDB:2ECH"
FT STRAND 19..21
FT /evidence="ECO:0007829|PDB:6LSQ"
FT TURN 23..25
FT /evidence="ECO:0007829|PDB:1RO3"
FT STRAND 37..39
FT /evidence="ECO:0007829|PDB:1RO3"
FT STRAND 44..46
FT /evidence="ECO:0007829|PDB:1RO3"
SQ SEQUENCE 186 AA; 20364 MW; 826D6A0F93251265 CRC64;
IGIAYNRGMC DPKKSVGTVM DHSTEHLSVA VAMAHEMGHN LGMDHDGNQC NCGGAGCVMS
EELIESRSYK FSDCSKNQYQ NYLTIYKPQC ILNQPLRTDT VSTPVSGNEL LQNSANPCYD
PLTCHPREGE QCESGPCCRN CKFLKEGTIC KRARGDDMDD YCNGKTCDCP RNPHKGPATA
KGSVLM
