Ribonuclease Inhibitor: Structure and Function

Abstract

Publisher Summary The mammalian ribonuclease inhibitor (RI) is a 50‐kDa cytosolic protein that binds to pancreatic‐type ribonucleases with femtomolar affinity and renders them inactive. The biological role of RI is not known in its entirety. The ribonucleases recognized by RI are secreted proteins, whereas RI resides exclusively in the cytosol. Nevertheless, RI affinity has been shown to be the primary determinant of ribonuclease cytotoxicity: Only ribonucleases that evade RI can kill a cell. In addition, the complex of RI with human angiogenin (ANG), which stimulates neovascularization by activating transcription in the nucleus, is the tightest of known RI.ribonuclease complexes. The chapter hypothesizes multiple biological roles for RI: (1) To protect cells from invading ribonucleases, (2) to regulate or terminate the activity of ribonuc leases with known intracellular functions, and ( 3) to monitor the oxidation state of the cell in response to factors such as aging and oxidative stress. RI possesses remarkable affinity for pancreatic‐type ribonucleases, despite their limited sequence identity. The resulting noncovalent complexes are some of the tightest known in biology. Details of the molecular interactions within RI.ribonuclease complexes have been elucidated from structural and biochemical investigations. Moreover, RI is known to be a sentry, protecting mammalian cells against invading ribonucleases, which abound in extracellular fluids. Still, many questions remain regarding the biological activity of RI.