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FOR THE RECORD

Changing the net charge from negative to positive makes ribonuclease Sa cytotoxic

¹ Department of Microbiology, Kazan State University, 420008 Kazan, Russia
² Rudolf-Buchheim-Institute of Pharmacology, Justus-Liebig-University of Giessen, 35392 Giessen, Germany
³ Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
⁴ Department of Biology, Grove City College, Grove City, Pennsylvania 16127, USA
⁵ Department of Medical Biochemistry and Genetics, Texas A&M University, College Station, Texas 77843, USA

Reprint requests to: C. Nick Pace, Department of Medical Biochemistry and Genetics, Texas A&M University, College Station, Texas 77843, USA; e-mail: nickpace{at}tamu.edu; fax: (979) 847-9481 or Alexander A. Makarov, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str. 32, 119991 Moscow, Russia; e-mail: aamakarov{at}genome.eimb.relarn.ru; fax: 7095-135-1405.

Ribonuclease Sa (pI = 3.5) from Streptomyces aureofaciens and its 3K (D1K, D17K, E41K) (pI = 6.4) and 5K (3K + D25K, E74K) (pI = 10.2) mutants were tested for cytotoxicity. The 5K mutant was cytotoxic to normal and v-ras-transformed NIH3T3 mouse fibroblasts, but RNase Sa and 3K were not. The structure, stability, and activity of the three proteins are comparable, but the net charge at pH 7 increases from -7 for RNase Sa to -1 for 3K and to +3 for 5K. These results suggest that a net positive charge is a key determinant of ribonuclease cytotoxicity. The cytotoxic 5K mutant preferentially attacks v-ras-NIH3T3 fibroblasts, suggesting that mammalian cells expressing the ras-oncogene are potential targets for ribonuclease-based drugs.

Keywords: Ribonuclease Sa; net charge; charge reversal mutants; cytotoxicity; v-ras-transformed fibroblasts

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