Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 426, Issue 17, Pages 3041-3056Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2014.06.007
Keywords
leucine-rich repeat (LRR); protein-protein interaction; reactive oxygen species (ROS); redox homeostasis; ribonuclease
Categories
Funding
- National Science Foundation Graduate Research Fellowship
- Department of Energy [DE-FC02-07ER64494]
- National Institutes of Health (NIH) [U01 GM098248]
- NIH [R01 CA073808, U54 GM074901, P50 GM064598]
- US Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-ENG-38]
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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 center dot RNase complexes to a resolution of 2.20, 2.21, and 1.92 angstrom, 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 Rls from mammalian species. Taken together, our results illuminate the structural and functional evolution of RI, along with its dynamic role in vertebrate biology. (C) 2014 Published by Elsevier Ltd.
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