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J. Biol. Chem., Vol. 281, Issue 35, 25622-25634, September 1, 2006

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Evolution and Function of Leukocyte RNase A Ribonucleases of the Avian Species, Gallus gallus^*

Takeaki Nitto¹, Kimberly D. Dyer, Meggan Czapiga, and Helene F. Rosenberg²

From the Laboratory of Allergic Diseases and Research Technologies Branch, NIAID, National Institutes of Health, Bethesda, Maryland 20892

In this study, we explore the evolution and function of two closely related RNase A ribonucleases from the chicken, Gallus gallus. Separated by 10 kb on chromosome 6, the coding sequences of RNases A-1 and A-2 are diverging under positive selection pressure (d_N > d_S) but remain similar to one another (81% amino acid identity) and to the mammalian angiogenins. Immunoreactive RNases A-1 and A-2 (both 16 kDa) were detected in peripheral blood granulocytes and bone marrow. Recombinant proteins are ribonucleolytically active (k_cat = 2.6 and 0.056 s^-1, respectively), and surprisingly, both interact with human placental ribonuclease inhibitor. RNase A-2, the more cationic (pI 11.0), is both angiogenic and bactericidal; RNase A-1 (pI 10.2) has neither activity. We demonstrated via point mutation of the catalytic His¹¹⁰ that ablation of ribonuclease activity has no impact on the bactericidal activity of RNase A-2. We determined that the divergent domains II (amino acids 71-76) and III (amino acids 89-104) of RNase A-2 are both important for bactericidal activity. Furthermore, we demonstrated that these cationic domains can function as independent bactericidal peptides without the tertiary structure imposed by the RNase A backbone. These results suggest that ribonucleolytic activity may not be a crucial constraint limiting the ongoing evolution of this gene family and that the ribonuclease backbone may be merely serving as a scaffold to support the evolution of novel, nonribonucleolytic proteins.

Received for publication, May 5, 2006 , and in revised form, June 26, 2006.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) DQ395275 [GenBank] and DQ395276 [GenBank] .

^* This work was supported by NIAID Intramural Funding Grant AI000942 (to H. F. R.) and by a Japan Society for the Promotion of Science Research Fellowship in Biomedical and Behavioral Research (to T. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Faculty of Medicine, Saga University, Nabeshima 5-1-1, Saga City, Saga 849-8501, Japan.

² To whom correspondence should be addressed: Bldg. 10, Rm. 11C215, Laboratory of Allergic Diseases, NIAID, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892-1883. Tel.: 301-402-1545; Fax: 301-402-1250; E-mail: hrosenberg{at}niaid.nih.gov.

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