Journal
PROTEIN SCIENCE
Volume 11, Issue 10, Pages 2522-2525Publisher
COLD SPRING HARBOR LAB PRESS
DOI: 10.1110/ps.0216702
Keywords
ribonuclease Sa; net charge; charge reversal mutants; cytotoxicity; v-ras-transformed fibroblasts
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Funding
- FIC NIH HHS [TW01058] Funding Source: Medline
- NIGMS NIH HHS [R01 GM037039] Funding Source: Medline
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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.
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