RT Journal Article
T1 Onconase dimerization through 3D domain swapping: structural investigations and increase in the apoptotic effect in cancer cells
A1 Fagagnini, Andrea
A1 Pica, Andrea
A1 Fasoli, Sabrina
A1 Montioli, Riccardo
A1 Donadelli, Massimo
A1 Cordani, Marco
A1 Butturini, Elena
A1 Acquasaliente, Laura
A1 Picone, Delia
A1 Gotte, Giovanni
AB 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.
PB Portland Press
SN 0264-6021
YR 2017
FD 2017
LK https://hdl.handle.net/20.500.14352/98862
UL https://hdl.handle.net/20.500.14352/98862
LA eng
NO 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
NO Ministry of University and Research (Italy)
DS Docta Complutense
RD 22 abr 2025