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How protein modifications influence apoptosis

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Members of the Faculty of Fundamental Medicine, the Lomonosov Moscow State University have described molecular mechanisms of how post-translational modifications of caspases, a family of proteolytic enzymes, exert their activation and function during apoptosis, an example of the process of programmed cell death. These results were published in the Trends in Cell Biology journal.

All known living organisms require constant cleaning from cells, which have already fulfilled their functions or became dangerous as a result of genetic damage, caused, for instance, by various toxic substances, ultraviolet radiation and other reasons. Self-destruction of such potentially dangerous cells is known as the process of programmed cell death, and apoptosis is the best-studied mode of cell death. It provides maintenance of tissue homeostasis and replacement of old cells with new ones. It is known that during 70 years of life epithelial cells in the mucosa of the gastrointestinal tractare renewed about 4000 times, and if cells which have fulfilled their functions are not destroyed, the length of intestinal mucosa within these 70 years could be equal 32 kilometers. For the same 70 years an organism produces about 3 tons of bone marrow cells.

Boris Zhivotovsky, Professor, the Head of the Laboratory of investigation of apoptosis mechanisms, where the project has been fulfilled, says: "Disturbances in various types of cell death have been implicated in multiple physiological and pathological processes. The consequence of too much cell death, because of the presence of few cells in the population, is resulting in loss of function and characterized by pathophysiological features of neurodegenerative disorders. Thus, excessive cell death destroys neurons and takes our brain in such a state, when a person loses at first short-term and then long-term memory. Development of Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, Huntington's chorea is more or less connected with "efficient" apoptotic cell death. Moreover, excessive death could cause hematologic, immunity-related and metabolic diseases. On the other hand, the consequence of too little cell death is associated with accumulation of many cells in population and some of them may be the wrong ones. Normally, a cell with a mutation should undergo the process of self-destruction but poor control and disturbance in apoptotic machinery cause emergence of malignant disease".

Activation and execution of apoptosis at molecular level are regulated by a family of cysteine proteases or caspases. Normally, they exist as inactive pro-caspases and should be cleaved in order to form an active tetramer. A huge number of various stimuli could be a signal for activation of self-destruction cellular program. Some of them can bind so called "death receptors" on the surface of the cell; DNA damage, various toxic compounds accumulation of wrongly folded proteins, absence of nutritional support, emergence of active forms of reactive oxygen species accumulated in cells, or warming-up of cells all can activate intracellular pathways leading to apoptosis. All above-mentioned factors contribute to the initiation of series of consecutive reactions involving caspase activation, so-called caspase cascade.

Understanding of the detailed mechanisms of caspase activation and regulation processes is tightly linked to the possibility to rationally influence apoptosis in order to get therapeutic advantages. The whole chain of reactions initiated within high molecular weight protein complexes via autoprocessing of so called initiator caspases, which then cleave and activate effector caspases. Appearance of these active proteases leads to destruction of various cellular structures, nuclear degradation and cellular disintegration with formation of apoptoticbodies. It is obvious that this complex system requires tiny control as accidental activation of caspases could lead to miserable consequences for a cell.

Alexey Zamaraev, a doctoral student and the first author of the article says: "Many proteins and secreted peptides undergo various structural changes as a result of post-translational modifications (PTM), namely after the end of their synthesis by ribosomes. Post-translational modifications mean covalent modifications of proteins after the end of their ribosomal synthesis. This process plays a key role in creation of protein heterogeneity, separation of identical proteins, their degradation, regulation of their activity and tissue-specific mechanisms of action Due to PTM one protein could fulfill different functions within a cell of the same organism. So, PTM creates an additional delicate level of regulation of protein function, which allows to respond more actively to the changes, occurring in the cells. Modifications take place in the endoplasmic reticulum and Golgi apparatus. For instance, special proteins, called kinases, transfer phosphoric acid residues to a precise amino-acid residue in a molecule of caspase, which leads to the change in the protein structure and inhibition or an activation of its functions. Phosphorylation of caspases, analyzed in details and described in the paper in the vast majority of cases results in changing of active center conformation and, consequently, inhibits activity of these proteins, thereby suppressing apoptotic process".

Eugenia Prokhorova, a student from the Lomonosov Moscow State University and project participant shares: "Post-translational modifications play a key role in the regulation of process of activation and further activity of caspases, acting as a switch between programmed cell death and cell survival. This role has been clearly shown in the article".

Inna Lavrik, Doctor of Chemistry, Professor, a Leading Researcher in the Laboratory of investigation of apoptosis mechanisms at the Faculty of Fundamental Medicine, the Lomonosov Moscow State University and the lead article author explains: "One of the most important conclusions has been made on the basis of bioinformatic analysis, which has shown for the first time a high conservation of some sites for phosphorylation of caspases, close to the active center of these proteases. This provides a clue for understanding general principles of regulation of these enzyme functioning and their role in apoptosis regulation".

In order to obtain results summarized in this article the scientists have conducted an analysis of more that 250 sources, which revealed main types of post-translational modifications with their classification in different types. Special attention has been given to the conditions, in which such modifications take place and the results of their activity, namely activation or inhibition of caspase activity. Along with the analysis of sources, the scientists have conducted a comparative bioinformatic analysis of amino acid sequences of each caspase from vertebrates and invertebrates. Besides that, the scientists have compared regions of post-translational modifications based on the protein tertiary structure. This analysis has helped to reveal not only conserved amino-acid residues, affected by modifications, but also predict the new ones. Moreover, bioinformatic analysis has allowed to make a conclusion about high similarity of some sites, dealing with phosphorylation of caspases in distantly related organisms.

On the basis of the received data one could predict new non-described sites of caspase modifications. Besides that, the received data could be used for design of specific inhibitors or activators, capable to regulate activity of caspases, and also for application of obtained data in possible treatment of diseases, such as neurodegeneration or cancer, both connected to the dysfunctions of these proteases.

Galina Kopeina, a Leading Researcher of the laboratory and project participant concludes: "Nowadays there are several anticancer drugs available, which suppress the activity of some groups of kinases (namely, the enzymes, which are in charge of post-translational phosphorylation). These are so called tyrosine kinase inhibitors, for instance, Afatinib, Bosutinib and so on. These drugs suppress activity of different groups of tyrosine kinases, which stimulate growth of malignant cells. In these conditions apoptosis pathway initiated, resulting in activation of caspases. Besides that, now usage of such a drug like Venetoclax (ABT-199) is recommended for treatment of some hematological tumors. This drug suppresses the function of anti-apoptotic proteins and also causes activation of caspases. Several pharmaceutical companies are working on elaboration of a new class of drugs, namely kinase inhibitors, which will be able to negatively influence the activity of caspases, thereby suppressing apoptosis, what is necessary for treatment of neurodegenerative diseases".

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