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J Mol Biol. 2014 Aug 26;426(17):3041-56. doi: 10.1016/j.jmb.2014.06.007. Epub 2014 Jun 15.

Functional evolution of ribonuclease inhibitor: insights from birds and reptiles.

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Graduate Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI 53706, USA.
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
Department of Biochemistry and Cell Biology and Department of Chemistry, Rice University, Houston, TX 77251, USA.
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address:


Ribonuclease inhibitor (RI) is a conserved protein of the mammalian cytosol. RI binds with high affinity to diverse secretory ribonucleases (RNases) and inhibits their enzymatic activity. Although secretory RNases are found in all vertebrates, the existence of a non-mammalian RI has been uncertain. Here, we report on the identification and characterization of RI homologs from chicken and anole lizard. These proteins bind to RNases from multiple species but exhibit much greater affinity for their cognate RNases than for mammalian RNases. To reveal the basis for this differential affinity, we determined the crystal structure of mouse, bovine, and chicken RI·RNase complexes to a resolution of 2.20, 2.21, and 1.92Å, respectively. A combination of structural, computational, and bioinformatic analyses enabled the identification of two residues that appear to contribute to the differential affinity for RNases. We also found marked differences in oxidative instability between mammalian and non-mammalian RIs, indicating evolution toward greater oxygen sensitivity in RIs from mammalian species. Taken together, our results illuminate the structural and functional evolution of RI, along with its dynamic role in vertebrate biology.


leucine-rich repeat (LRR); protein–protein interaction; reactive oxygen species (ROS); redox homeostasis; ribonuclease

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