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The role of electrostatic interactions in the antitumor activity of dimeric RNases
Eugenio Notomista1, José Miguel Mancheño, Orlando Crescenzi
1Dipartimento di Biologia Strutturale e Funzionale, Università di Napoli Federico II, Napoli, Italy.
Abstract:
The cytotoxic action of some ribonucleases homologous to bovine pancreatic RNase A, the superfamily prototype, has interested and intrigued investigators. Their ribonucleolytic activity is essential for their cytotoxic action, and their target RNA is in the cytosol. It has been proposed that the cytosolic RNase inhibitor (cRI) plays a major role in determining the ability of an RNase to be cytotoxic. However, to interact with cRI RNases must reach the cytosol, and cross intracellular membranes. To investigate the interactions of cytotoxic RNases with membranes, cytotoxic dimeric RNases resistant, or considered to be resistant to cRI, were assayed for their effects on negatively charged membranes. Furthermore, we analyzed the electrostatic interaction energy of the RNases complexed in silico with a model membrane. The results of this study suggest that close correlations can be recognized between the cytotoxic action of a dimeric RNase and its ability to complex and destabilize negatively charged membranes.
Insights
Cytotoxic ribonucleases that resist cytosolic RNase inhibitor (cRI) can destabilize cell membranes. This membrane interaction correlates with their cytotoxic action, suggesting a novel mechanism for RNase-induced cell death.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Cytotoxic ribonucleases (RNases) homologous to bovine pancreatic RNase A are of significant interest.
- Their cytotoxic action relies on ribonucleolytic activity targeting cytosolic RNA.
- The cytosolic RNase inhibitor (cRI) is thought to be crucial for RNase cytotoxicity, but RNases must first reach the cytosol by crossing cell membranes.
Purpose of the Study:
- To investigate the interaction of cytotoxic RNases with cell membranes.
- To explore the role of membrane interaction in the cytotoxic action of RNases resistant to cRI.
Main Methods:
- Assaying cytotoxic dimeric RNases (resistant to cRI) for their effects on negatively charged membranes.
- Analyzing the electrostatic interaction energy between RNases and a model membrane using in silico methods.
Main Results:
- Cytotoxic dimeric RNases demonstrated the ability to complex with and destabilize negatively charged membranes.
- A strong correlation was observed between a dimeric RNase's cytotoxic action and its capacity to interact with and destabilize membranes.
Conclusions:
- The ability of cytotoxic dimeric RNases to interact with and destabilize negatively charged membranes is closely linked to their cytotoxic effects.
- Membrane destabilization may represent a key mechanism contributing to the cytotoxicity of certain RNases, particularly those resistant to cRI.
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