Sulfotyrosine-Mediated Recognition of Human Thrombin by a Tsetse Fly Anticoagulant Mimics Physiological Substrates

• Type: Article in International Scientific Journal
• Date: 2021

Authors

Calisto, BM (Author) Other; Ripoll Rozada, J (Author) Other; Dowman, LJ (Author) Other; Franck, C (Author) Other; Agten, SM (Author) Other; Parker, BL (Author) Other; Veloso, RC (Author) Other; Nuno Vale (Author) FMUP; Paula Gomes (Author) FCUP; de Sanctis, D (Author) Other; Payne, RJ (Author) Other; Pereira, PJB (Author) Other

Journal

Title: Cell Chemical Biology

Vol. 28

Pages: 26-+

ISSN: 2451-9448

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 14 Citations

Scopus - 14 Citations

Other information

Authenticus ID: P-00S-YN2

DOI: 10.1016/j.chembiol.2020.10.002

Abstract (EN): Despite possessing only 32 residues, the tsetse thrombin inhibitor (TTI) is among the most potent anticoagulants described, with sub-picomolar inhibitory activity against thrombin. Unexpectedly, TTI isolated from the fly is 2000-fold more active and 180 Da heavier than synthetic and recombinant variants. We predicted the presence of a tyrosine O-sulfate post-translational modification of TTI, prompting us to investigate the effect of the modification on anticoagulant activity. A combination of chemical synthesis and functional assays was used to reveal that sulfation significantly improved the inhibitory activity of TTI against thrombin. Using X-ray crystallography, we show that the N-terminal sulfated segment of TTI binds the basic exosite II of thrombin, establishing interactions similar to those of physiologic substrates, while the C-terminal segment abolishes the catalytic activity of thrombin. This non-canonical mode of inhibition, coupled with its potency and small size, makes TTI an attractive scaffold for the design of novel antithrombotics.

Language: English

Type (Professor's evaluation): Dissemination

No. of pages: 16