Binding To Ribonucleases
The affinity of RI for ribonucleases is perhaps the highest for any protein-protein interaction; the dissociation constant of the RI-RNase A complex is roughly 20 fM under physiological conditions while that for the RI-angiogenin complex is even smaller (<1 fM). Remarkably, RI is able to bind a wide variety of RNases, despite having low sequence identity. Structural studies indicate that RNases bind like a "cork in the bottle", associating especially with the C-terminal end of RI; the interaction is largely electrostatic but also buries a lot of surface area (>25 nm2). Efforts to mutate RNases to lower their affinity for RI while maintaining their enzymatic activity have had limited success. However, mammalian RI seems unable to bind a few amphibian ribonucleases, such as ranpirnase (also known as Onconase).
RI's affinity for ribonucleases is important, since ribonucleases have cytotoxic and cytostatic effects (especially against cancer cells), and are under investigation as potential cancer therapeutics. Successful evasion of the ubiquitous RI would be essential for the success of a ribonuclease drug, (since it would be ineffective bound to RI). The frog protein Onconase is under investigation for treatment of skin cancers; unfortunately, the antigenicity of amphibian proteins makes them unsuitable for treating internal human cancers. Modifications of human ribonucleases that evade RI but retain their enzymatic activity have also been studied.
Read more about this topic: Ribonuclease Inhibitor
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