Ribonuclease inhibitor

Ribonuclease inhibitor (RI) is a large (~450 residues, ~49 kDa), acidic (pI ~4.7), leucine-rich repeat protein that forms extremely tight complexes with certain ribonucleases. It is a major cellular protein, comprising ~0.1% of all cellular protein by weight, and appears to play an important role in regulating the lifetime of RNA.

RI has a surprisingly high cysteine content (~6.5%, cf. 1.7% in typical proteins) and is sensitive to oxidation. RI is also rich in leucine (21.5%, compared to 9% in typical proteins) and commensurately lower in other hydrophobic residues, esp. valine, isoleucine, methionine, tyrosine, and phenylalanine.

tructure

RI is the classic leucine-rich repeat protein, consisting of alternating α-helices and β-strands along its backbone. These secondary structure elements wrap around in a curved, right-handed solenoid that resembles a horseshoe. The parallel β-strands and α-helices form the inner and outer wall of the horseshoe, respectively. The structure appears to be stabilized by buried asparagines at the base of each turn, as it passes from α-helix to β-strand. The αβ repeats alternate between 28 and 29 residues in length, effectively forming a 57-residue unit that corresponds to its genetic structure (each exon codes for a 57-residue unit).

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 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.

References

* Shapiro R. (2001) "Cytoplasmic Ribonuclease Inhibitor", "Methods Enzymol.", 341, 611-628.

* Kobe B and Deisenhofer J. (1993) "Crystal structure of porcine ribonuclease inhibitor, a protein with leucine-rich repeats", "Nature", "'366", 751-756.

* Kobe B and Deisenhofer J. (1995) "A structural basis of the interactions between leucine-rich repeats and protein ligands", "Nature", 374, 183-186.

* Kobe B and Deisenhofer J. (1996) "Mechanism of ribonuclease inhibition by ribonuclease inhibitor protein based on the crystal structure of its complex with ribonuclease A" "J. Mol. Biol.", 264, 1028-1043.

* Papageorgiou AC, Shapiro R and Acharya KR. (1997) "Molecular recognition of human angiogenin by placental ribonuclease inhibitor - an X-ray crystallographic study at 2.0 Å resolution", "EMBO J.", 16, 5162-5177.

* Suzuki M, Saxena SK, Boix E, Prill RJ, Vasandani VM, Ladner JE, Sung C and Youle RJ. (1999) "Engineering receptor-rediated cytotoxicity into human ribonucleases by steric blockade of inhibitor interaction", "Nature Biotech.", 17, 265-270.

* Shapiro R, Ruiz-Gutierrez M and Chen CZ. (2000) 'Analysis of the Interactions of Human Ribonuclease Inhibitor with Angiogenin and Ribonuclease A by Mutagenesis:Importance of Inhibitor Residues Inside versus Outside the C-terminal "Hot Spot"', "J. Mol. Biol.", 302, 497-519.

* Bretscher LE, Abel RL and Raines RT. (2000) "A Ribonuclease A Variant with Low Catalytic Activity but High Cytotoxicity", "J. Biol. Chem.", 275, 9893-9896.


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