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The cytotoxic action of some ribonucleases homologous to bovine pancre-atic 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. | ỊFEBS Journal The role of electrostatic interactions in the antitumor activity of dimeric RNases Eugenio Notomista1 Jose Miguel Mancheno2 Orlando Crescenzi3 Alberto Di Donato1 Jose Gavilanes4 and Giuseppe D Alessio1 1 Dipartimento di Biologia Strutturale e Funzionale University di Napoli Federico II Napoli Italy 2 Grupo de Cristalografia Macromolecular y Biologia Estructural Instituto Rocasolano Madrid Spain 3 Dipartimento di Chimica Universita di Napoli Federico II Napoli Italy 4 Departamento de Bioquimica y Biologia Molecular I Universidad Complutense Madrid Spain Keywords antitumor RNases electrostatic interactions electrostatic interaction energy RNases transport through membranes Correspondence G. D Alessio Dipartimento di Biologia Strutturale e Funzionale University di Napoli Federico II Via Cinthia I-80126 Napoli Italy Fax 39 081 679159 Tel 39 081 679157 E-mail dalessio@unina.it Received 12 April2006 revised 31 May 2006 accepted 12 June 2006 doi 10.1111 j.1742-4658.2006.05373.x 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
