Onconase® (ONC), a protein extracted from the oocytes of the Rana pipiens frog, is a monomeric member of the secretory ‘pancreatic-type’ RNase superfamily. Interestingly, ONC is the only monomeric ribonuclease endowed with a high cytotoxic activity. In contrast with other monomeric RNases, ONC displays a high cytotoxic activity. In this work, we found that ONC spontaneously forms dimeric traces and that the dimer amount increases about four times after lyophilization from acetic acid solutions. Differently from RNase A (bovine pancreatic ribonuclease) and the bovine seminal ribonuclease, which produce N- and C-terminal domain-swapped conformers, ONC forms only one dimer, here named ONC-D. Cross-linking with divinylsulfone reveals that this dimer forms through the three-dimensional domain swapping of its N-termini, being the C-terminus blocked by a disulfide bond. Also, a homology model is proposed for ONC-D, starting from the well-known structure of RNase A N-swapped dimer and taking into account the results obtained from spectroscopic and stability analyses. Finally, we show that ONC is more cytotoxic and exerts a higher apoptotic effect in its dimeric rather than in its monomeric form, either when administered alone or when accompanied by the chemotherapeutic drug gemcitabine. These results suggest new promising implications in cancer treatment.
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A 3D rendering of a mitochondrion. In this issue of the Biochemical Journal, Monteuuis et al. report that a conserved mammalian mitochondrial isoform of acetyl-CoA carboxylase ACC1 provides the malonyl-CoA essential for mitochondrial biogenesis in tandem with the mitochondrial malonyl-CoA synthetase ACSF3; see pages 3783–3797 for details.
Onconase dimerization through 3D domain swapping: structural investigations and increase in the apoptotic effect in cancer cells*
Andrea Fagagnini, Andrea Pica, Sabrina Fasoli, Riccardo Montioli, Massimo Donadelli, Marco Cordani, Elena Butturini, Laura Acquasaliente, Delia Picone, Giovanni Gotte; Onconase dimerization through 3D domain swapping: structural investigations and increase in the apoptotic effect in cancer cells. Biochem J 15 November 2017; 474 (22): 3767–3781. doi: https://doi.org/10.1042/BCJ20170541
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