title: [Cytotoxicity mechanism of the RNase Sa cationic mutants involves inhibition of potassium current through Ca2+-activated channels].
abstract: Bacterial ribonucleases (RNases) are considered to be potential anticancer agents. One of most important determinants of RNase cytotoxicity is the net charge of the molecule. In this work a set of mutants of the RNase from Streptomyces aureofaciens (RNase Sa), differing in the net charge of the protein molecules (from -7 to +6) and localization of additional positive charge at the N- or C-terminus of the molecule is used to study inhibition of cell growth. It has been found that the mutants of RNase with increased cationicity most effectively inhibit the growth of HEKhSK4 cells. Additional positive charge at the C-terminus of the molecule also increases the cytotoxic properties of RNases. It has been shown that RNase cytotoxicity correlated with the level of inhibition of the K+-current in cells.
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991 Russia;|mitkevich@gmail.com.
authors.forename: V A
authors.initials: VA
authors.lastname: Mitkevich
authors.affiliation: Texas A&M University, College Station, Texas, 77843 United States.
authors.forename: C N
authors.initials: CN
authors.lastname: Pace
authors.affiliation: Medical Science Division, University of Oxford, Oxford OX3 9DU, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Koschinski
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991 Russia;
authors.forename: A A
authors.initials: AA
authors.lastname: Makarov
authors.affiliation: Department of Microbiology, Kazan Federal Volga-Region University, Kazan, 420008 Russia.
authors.forename: O N
authors.initials: ON
authors.lastname: Ilinskaya
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D017136:Ion Transport; D009154:Mutation; D011188:Potassium / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012260:Ribonucleases / Q000737:chemistry / Q000235:genetics / Q000633:toxicity*; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D055672:Static Electricity; D013304:Streptomyces aureofaciens / Q000201:enzymology
chemical_list: D051640:Small-Conductance Calcium-Activated Potassium Channels; D012260:Ribonucleases; D011188:Potassium
keywords: Ca^(2+)-activated potassium channels; cationic RNases; cytotoxicity; net charge of proteins