A synapomorphic disulfide bond is critical for the conformational stability and cytotoxicity of an amphibian ribonuclease

Onconase(R) (ONC) is a homolog of ribonuclease A (RNase A) that has unusually high conformational stability and is toxic to human cancer cells in vitro and in vivo. ONC and its amphibian homologs have a C-terminal disulfide bond, which is absent in RNase A. Replacing this cystine with a pair of alanine residues greatly decreases the conformational stability of ONC, In addition, the C87A/C104A variant is 10-fold less toxic to human leukemia cells. These data indicate that the synapomorphic disulfide bond of ONC is an important determinant of its cytotoxicity. (C) 2000 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.