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Article

Novel Apoptotic Mediators Identified by Conservation of Vertebrate Caspase Targets

1
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, 142290 Moscow, Russia
2
Center fof Life Sciences, Skolkovo Institute of Science and Technology, 121205 Moscow, Russia
3
Center for Neurobiology and Brain Restoration, Skolkovo Institute of Science and Technology, 121205 Moscow, Russia
4
Institute of Mathematical Problems of Biology, Keldysh Institute of Applied Mathematics, Russian Academy of Sciences, Pushchino, 142290 Moscow, Russia
*
Authors to whom correspondence should be addressed.
These two authors contributed equally.
Biomolecules 2020, 10(4), 612; https://doi.org/10.3390/biom10040612
Received: 25 March 2020 / Revised: 8 April 2020 / Accepted: 13 April 2020 / Published: 15 April 2020
(This article belongs to the Special Issue Mechanisms of Cell Death in Disease: A New Therapeutic Opportunity)
Caspases are proteases conserved throughout Metazoans and responsible for initiating and executing the apoptotic program. Currently, there are over 1800 known apoptotic caspase substrates, many of them known regulators of cell proliferation and death, which makes them attractive therapeutic targets. However, most caspase substrates are by-standers, and identifying novel apoptotic mediators amongst all caspase substrates remains an unmet need. Here, we conducted an in silico search for significant apoptotic caspase targets across different species within the Vertebrata subphylum, using different criteria of conservation combined with structural features of cleavage sites. We observed that P1 aspartate is highly conserved while the cleavage sites are extensively variable and found that cleavage sites are located primarily in coiled regions composed of hydrophilic amino acids. Using the combination of these criteria, we determined the final list of the 107 most relevant caspase substrates including 30 novel targets previously unknown for their role in apoptosis and cancer. These newly identified substrates can be potential regulators of apoptosis and candidates for anti-tumor therapy. View Full-Text
Keywords: caspases; apoptosis; cleavage site; N-degron pathway; conservation; evolution; regulation caspases; apoptosis; cleavage site; N-degron pathway; conservation; evolution; regulation
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  • Externally hosted supplementary file 1
    Doi: https://doi.org/10.7910/DVN/OT9VSD
    Link: https://doi.org/10.7910/DVN/OT9VSD
    Description: Supplementary materials are deposited at Harvard Dataverse under DOI: https://doi.org/10.7910/DVN/OT9VSD Supplementary figures: Figure S1: Distribution of P1 glutamate cleavage sites in three vertebrate classes, Figure S2: Principal coordinate analysis (PCoA) of cleavage sites and 60 amino acid sequences, Figure S3: Hierarchical clustering of cleavage sites, Figure S4: Hierarchical clustering of 60 amino acid sequences, Figure S5: Correlation between hydrophobicity of cleavage site surroundings and cleavage rates for human caspase targets, Figure S6: Distribution of P1’ destabilizing amino acid residues among cleavage sites and among vertebrates, Supplementary Tables: Table S1: Human caspase targets, Table S2: Description of orthologous caspase targets, Table S3: Percentage of P1 glutamate cleavage sites in species, Table S4: Summary of conservation criteria, for all human and orthologous targets, Table S5: Secondary structure predictions for human caspase targets, Table S6: Comparison of secondary structure prediction results with previous studies, Table S7: Percentage of P1 prime destabilizing amino acids according to the Arg/N-degron pathway, at the species level, Table S8: Subset of caspase targets most important in the apoptotic program
MDPI and ACS Style

Gubina, N.; Leboeuf, D.; Piatkov, K.; Pyatkov, M. Novel Apoptotic Mediators Identified by Conservation of Vertebrate Caspase Targets. Biomolecules 2020, 10, 612. https://doi.org/10.3390/biom10040612

AMA Style

Gubina N, Leboeuf D, Piatkov K, Pyatkov M. Novel Apoptotic Mediators Identified by Conservation of Vertebrate Caspase Targets. Biomolecules. 2020; 10(4):612. https://doi.org/10.3390/biom10040612

Chicago/Turabian Style

Gubina, Nina, Dominique Leboeuf, Konstantin Piatkov, and Maxim Pyatkov. 2020. "Novel Apoptotic Mediators Identified by Conservation of Vertebrate Caspase Targets" Biomolecules 10, no. 4: 612. https://doi.org/10.3390/biom10040612

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