Abstract
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.
Highlights
Caspases are cysteine proteases that mediate a vast array of cellular processes and are best known for their prominent role in initiation of inflammation and executing programmed cell death
We conducted an in silico search for significant apoptotic caspase targets using different criteria of conservation combined with structural features of cleavage sites
The aim of this study was to identify previously unknown apoptotic caspase substrates with a high functional significance in the apoptotic program using different parameters of conservation of the substrate as an indicator of importance
Summary
Caspases are cysteine proteases that mediate a vast array of cellular processes and are best known for their prominent role in initiation of inflammation and executing programmed cell death. Caspase cleavage can result in protein degradation, activation or a change in the cellular localization of the protein, depending on the newly generated N-terminal signal [2]. Manipulation of caspase activity was explored in cancer therapy to increase tumor cell death or, to prevent apoptosis in diseases such as chronic hepatitis C virus (HCV) infection or Alzheimer’s disease [6]. A rigorous study of caspase substrates will serve to identify appropriate drug targets, especially if caspases and upstream factors of apoptosis are not available for direct manipulation [7]
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