Flexibility of the thrombin-activatable fibrinolysis inhibitor pro-domain enables productive binding of protein substrates

We have previously reported that thrombin-activatable fibrinolysis inhibitor (TAFI) exhibits intrinsic proteolytic activity toward large peptides. The structural basis for this observation was clarified by the crystal structures of human and bovine TAFI. These structures evinced a significant rotation of the pro-domain away from the catalytic moiety when compared with other pro-carboxypeptidases, thus enabling access of large peptide substrates to the active site cleft. Here, we further investigated the flexible nature of the pro-domain and demonstrated that TAFI forms productive complexes with protein carboxypeptidase inhibitors from potato, leech, and tick (PCI, LCI, and TCI, respectively). We determined the crystal structure of the bovine TAFI-TCI complex, revealing that the pro-domain was completely displaced from the position observed in the TAFI structure. It protruded into the bulk solvent and was disordered, whereas TCI occupied the position previously held by the pro-domain. The authentic nature of the presently studied TAFI-inhibitor complexes was supported by the trimming of the C-terminal residues from the three inhibitors upon complex formation. This finding suggests that the inhibitors interact with the active site of TAFI in a substrate-like manner. Taken together, these data show for the first time that TAFI is able to form a bona fide complex with protein carboxypeptidase inhibitors. This underlines the unusually flexible nature of the pro-domain and implies a possible mechanism for regulation of TAFI intrinsic proteolytic activity in vivo.

Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.

We have previously reported that thrombin-activatable fibrinolysis inhibitor (TAFI) exhibits intrinsic proteolytic activity toward large peptides.

Узнайте, как это исследование связано с клинической практикой

More peer-reviewed studies in Геномика и протеомика.

• 434 Salivary Proteins — Integrated Proteomics of Hirudo medicinalis — Liu et al. (2019)
• Medicinal Leech Genome Assembly — Anticoagulant Gene Catalog — Kvist et al. (2020)
• Effects of hirudotherapy on liver functions, lipid profile, and insulin sensitivity in rats with metabolic syndrome — Bilden A et al. (2026)
• Efficacy and Safety of Hirudotherapy for Improving Sperm Quality Parameters in Male Infertility: A Randomized Controlled Trial — Abtahi-Forooshani M et al. (2026)
• Hirudotherapy in Wound Healing — Nair H et al. (2022)
• [Medicinal leeches and hirudotherapy] — Gödekmerdan A et al. (2011)
• [Cutaneous pseudolymphoma after hirudotherapy : Case report and review] — Hanner S et al. (2022)
• HIRUDOTHERAPY IN PRESBYACUZIS PRAECOX IN CLEAN-UP WORKERS AFTER THE CHORNOBYL ACCIDENT DURING THE POST-CATASTROPHE YEARS — Zabolotnyi D, Mishchanchuk N (2019)
• Hirudotherapy (medicinal leeches) for treatment of upper airway obstruction in a dog — Trenholme H, Masseau I, Reinero C (2021)
• Leech therapy — Yantis M, O'Toole K, Ring P (2009)

Browse all ASH-analysed research →