Novel Apoptotic Mediators Identified by Conservation of Vertebrate Caspase Targets

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.

The IMPB RAS is 50 years old. Laboratory of Data Processing

“…Сервис доступен по адресу http://protdb.org. Создана база данных, содержащая сайты щепления человека, а также ортологичные сайты, найденные в других организмах [10]. Разработан ряд критериев консервативности.…”

Inhibition of Proliferation and Induction of Apoptosis in Prostatic Carcinoma DU145 Cells by Polysaccharides from Yunnan Rosa roxburghii Tratt

“…Organismal development and function requires multiple and accurate signal transduction pathways to ensure that proper balance between cell proliferation, differentiation, inactivation, and death is achieved [18]. Caspases are proteases conserved for initiating and executing the apoptotic program [19]. The cell death pathway, primarily mediated by the caspase family's proteolytic enzymes, is activated by internal or external stimuli.…”