Bovine seminal ribonuclease and its special features: When two is better than one

Abstract

Bovine Seminal Ribonuclease (BS-RNase) is a structurally well-characterized protein which has been isolated in Naples in the sixties. It is a homodimer whose subunits are linked by two disulfide bridges and exists as an equilibrium mixture of two isomers, with and without swapping of the N-termini. The protein has an enzymatic activity very similar to that of the well-known Ribonuclease A, but it also displays a potent antitumor activity. We describe our current understanding of how BS-RNase exerts its cytotoxicity against malignant cells, which is strictly related to the RNA hydrolysis occurring in the host cytosol. Structural and biochemical data collected on the BS-RNase isoforms and on some mutants suggest that the swapped form is responsible for the citotoxicity, mainly because its compact 3D structure allows the protein to evade the RNase inhibitor, a protein acting as a cell sentry against exogenous ribonucleases. Structural comparisons among dimeric ribonucleases and site-directed mutagenesis studies suggest that only a few residues are critical to stabilize this compact structure even in the cytosol, where the reducing environment promotes the selective cleavage of the interchain disulfides. However, further engineering studies are needed to develop new potential anticancer drugs based on BS-RNase and its derivatives.