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Toxins 2016, 8(4), 110; doi:10.3390/toxins8040110

The Kunitz-Type Protein ShPI-1 Inhibits Serine Proteases and Voltage-Gated Potassium Channels

1
Centro de Estudio de Proteínas, Facultad de Biología, Universidad de la Habana, Calle 25 No. 455, 10400 La Habana, Cuba
2
Laboratory of Toxicology and Pharmacology, KU Leuven, Campus Gasthuisberg O&N2, Herestraat 49, P.O. Box 922, B-3000 Leuven, Belgium
3
Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, Madrid E-28029, Spain
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editors: Rong Chen and Yingliang Wu
Received: 10 March 2016 / Revised: 4 April 2016 / Accepted: 5 April 2016 / Published: 13 April 2016
(This article belongs to the Special Issue Animal Toxins and Biological Ion Channels)
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Abstract

The bovine pancreatic trypsin inhibitor (BPTI)-Kunitz-type protein ShPI-1 (UniProt: P31713) is the major protease inhibitor from the sea anemone Stichodactyla helianthus. This molecule is used in biotechnology and has biomedical potential related to its anti-parasitic effect. A pseudo wild-type variant, rShPI-1A, with additional residues at the N- and C-terminal, has a similar three-dimensional structure and comparable trypsin inhibition strength. Further insights into the structure-function relationship of rShPI-1A are required in order to obtain a better understanding of the mechanism of action of this sea anemone peptide. Using enzyme kinetics, we now investigated its activity against other serine proteases. Considering previous reports of bifunctional Kunitz-type proteins from anemones, we also studied the effect of rShPI-1A on voltage-gated potassium (Kv) channels. rShPI-1A binds Kv1.1, Kv1.2, and Kv1.6 channels with IC50 values in the nM range. Hence, ShPI-1 is the first member of the sea anemone type 2 potassium channel toxins family with tight-binding potency against several proteases and different Kv1 channels. In depth sequence analysis and structural comparison of ShPI-1 with similar protease inhibitors and Kv channel toxins showed apparent non-sequence conservation for known key residues. However, we detected two subtle patterns of coordinated amino acid substitutions flanking the conserved cysteine residues at the N- and C-terminal ends. View Full-Text
Keywords: protease inhibitor; Kv channel inhibitor; sea anemone; toxin; Kunitz-type protein protease inhibitor; Kv channel inhibitor; sea anemone; toxin; Kunitz-type protein
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MDPI and ACS Style

García-Fernández, R.; Peigneur, S.; Pons, T.; Alvarez, C.; González, L.; Chávez, M.A.; Tytgat, J. The Kunitz-Type Protein ShPI-1 Inhibits Serine Proteases and Voltage-Gated Potassium Channels. Toxins 2016, 8, 110.

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