Therostasin, a Novel Clotting Factor Xa Inhibitor from the
Rhynchobdellid Leech, Theromyzon tessulatum*
Vincent
Chopin
§,
Michel
Salzet§¶,
Jean-luc
Baert
,
Franck
Vandenbulcke,
Pierre-Eric
Sautière,
Jean-Pierre
Kerckaert**, and
Jean
Malecha
From the Laboratoire d'Endocrinologie des
Annélides, UPRES-A 8017 CNRS, SN3, Université des Sciences
et Technologie de Lille, F-59655 Villeneuve d'Ascq Cédex,
France, the Institut de Biologie de Lille, CNRS-UMR 8526, rue du
Professeur Calmette, F-59019 Lille, France, and the ** Laboratoire
d'Oncohématologie, Unité 524, INSERM, place de Verdun,
F-59045 Lille, France
Therostasin is a potent naturally occurring
tight-binding inhibitor of mammalian Factor Xa (Ki,
34 pM), isolated from the rhynchobdellid leech
Theromyzon tessulatum. Therostasin is a cysteine-rich
protein (8991 Da) consisting of 82 amino acid residues with 16 cysteine
residues. Its amino acid sequence has been determined by a combination
of techniques, including Edman degradation, enzymatic cleavage, and
matrix-assisted laser desorption/ionization time-of-flight mass
spectrometry (MALDI-TOF MS) on the native and s-
-pyridylethylated
compound. Sequence analysis reveals that it shares no significant
homology with other Factor Xa inhibitors except for the putative
reactive site. Moreover, it contains a signature pattern for proteins
of the endothelin family, potent vasoconstrictors isolated in mammal
and snake venom. Therostasin cDNA (825 bp) codes for a polypeptide
of 82 amino acid residues preceded by 19 residues, representing a
signal peptide sequence. As for the other known inhibitors of Factor
Xa, therostasin is expressed and stored in the cells of the leech
salivary glands.
*
This work was supported in part by the Federal European
Development Economic Regional, Conseil Régional Nord-Pas
de Calais, CNRS, Agence National pour la Valorisation de la Recherche,
and by National Institutes of Health-Fogarty International Grant 00045.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF239803.
The nucleotide sequence reported in this paper has
been submitted to the Swiss Protein Database under Swiss-Prot accession no. P82355.
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