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Abstract

pH-Dependent Specificity of Papain-Like Cysteine Proteases Is Determined by S1 Binding Pocket †

1
Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia
2
Research Center for Translational Medicine, Sirius University of Science and Technology, 354340 Sochi, Russia
3
Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119234 Moscow, Russia
4
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119234 Moscow, Russia
*
Authors to whom correspondence should be addressed.
Presented at the 2nd International Electronic Conference on Biomolecules: Biomacromolecules and the Modern World Challenges, 1–15 November 2022; Available online: https://iecbm2022.sciforum.net/.
Biol. Life Sci. Forum 2022, 20(1), 21; https://doi.org/10.3390/IECBM2022-13385
Published: 1 November 2022

Abstract

:
Papain-like cysteine proteases (PLCPs) are widely expressed enzymes, the main function of which is low-specific-protein turnover in the acidic conditions of lysosomes. Additionally, these proteases provide specific functions in other compartments such as cytosol, nucleus, and extracellular space. The specificity of each protease to its substrates mainly depends on the patterns of the amino acids in the binding cleft. This specificity is highly regulated by media conditions and the presence of accessory proteins. In this study, we examined structural aspects, ensuring the pH-dependent substrate specificity of PLCPs. Experiments employing fluorogenic peptide substrates demonstrated that plant PLCPs and human cathepsins possess a pH-dependent specificity for the residue in the P1 position. X-ray crystallographic studies and molecular simulations allowed the overall structure determination of the enzymes to predict residues in the S1 binding pocket, which can form electrostatic contacts with the substrates. Sequence analysis established the variability of these residues among PLCPs. Based on the obtained data, we designed a peptide inhibitor for human cathepsin L and described its inhibitory potential. As a conclusion, we stated that the S1 binding pocket defines specific pH-dependent recognition of substrates by PLCPs, ensuring multiple physiological functions of these proteases. This work was supported by the Russian Science Foundation (grant No. 22-25-00648).

Supplementary Materials

The presentation material of this work is available online at https://www.mdpi.com/article/10.3390/IECBM2022-13385/s1.

Author Contributions

Conceptualization, L.S. and A.Z.J.; methodology, L.S., A.G. and E.Z.; software, A.Z. and A.G.; investigation, A.P., A.Z., N.G., V.M., and M.S.; resources, A.G., E.Z., and A.Z.J.; data curation, A.Z.J.; writing—original draft preparation, A.P.; writing—review and editing, L.S. and A.Z.J.; visualization, A.P. and A.Z.; supervision, L.S. and A.Z.J.; project administration, L.S. and A.Z.J.; funding acquisition, L.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Russian Science Foundation grant number 22-25-00648.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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MDPI and ACS Style

Petushkova, A.; Zalevsky, A.; Gorokhovets, N.; Makarov, V.; Savvateeva, L.; Serebryakova, M.; Golovin, A.; Zernii, E.; Zamyatnin, A., Jr. pH-Dependent Specificity of Papain-Like Cysteine Proteases Is Determined by S1 Binding Pocket. Biol. Life Sci. Forum 2022, 20, 21. https://doi.org/10.3390/IECBM2022-13385

AMA Style

Petushkova A, Zalevsky A, Gorokhovets N, Makarov V, Savvateeva L, Serebryakova M, Golovin A, Zernii E, Zamyatnin A Jr. pH-Dependent Specificity of Papain-Like Cysteine Proteases Is Determined by S1 Binding Pocket. Biology and Life Sciences Forum. 2022; 20(1):21. https://doi.org/10.3390/IECBM2022-13385

Chicago/Turabian Style

Petushkova, Anastasiia, Arthur Zalevsky, Neonila Gorokhovets, Vladimir Makarov, Lyudmila Savvateeva, Marina Serebryakova, Andrey Golovin, Evgeni Zernii, and Andrey Zamyatnin, Jr. 2022. "pH-Dependent Specificity of Papain-Like Cysteine Proteases Is Determined by S1 Binding Pocket" Biology and Life Sciences Forum 20, no. 1: 21. https://doi.org/10.3390/IECBM2022-13385

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