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J. Biol. Chem., Vol. 282, Issue 3, 2101-2115, January 19, 2007

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The C-terminal Domains of Vertebrate CstF-64 and Its Yeast Orthologue Rna15 Form a New Structure Critical for mRNA 3'-End Processing^*

Xiangping Qu¹, Jose-Manuel Perez-Canadillas¹², Shipra Agrawal³, Julia De Baecke, Hailing Cheng⁴, Gabriele Varani⁵, and Claire Moore⁶

From the Department of Molecular Microbiology, Tufts University School of Medicine and the Sackler Graduate School of Biomedical Sciences, Boston, Massachusetts 02111 and the Department of Biochemistry and Department of Chemistry, University of Washington, Seattle, Washington 98195

Yeast Rna15 and its vertebrate orthologue CstF-64 play critical roles in mRNA 3 '-end processing and in transcription termination downstream of poly(A) sites. These proteins contain N-terminal domains that recognize the poly(A) site, but little is known about their highly conserved C-terminal regions. Here we show by NMR that the C-terminal domains of CstF-64 and Rna15 fold into a three-helix bundle with an uncommon topological arrangement. The structure defines a cluster of evolutionary conserved yet exposed residues we show to be essential for the interaction between Pcf11 and Rna15. Furthermore, we demonstrate that this interaction is critical for the function of Rna15 in 3 '-end processing but dispensable for transcription termination. The C-terminal domain of the Rna15 homologue Pti1 contains critical sequence alterations within this region that are predicted to prevent Pcf11 interaction, providing an explanation for the distinct functions of these two closely related proteins in the 3 '-end formation of RNA polymerase II transcripts. These results define the role of the C-terminal half of Rna15 and provide insight into the network of protein/protein interactions responsible for assembly of the 3 '-end processing apparatus.

Received for publication, October 24, 2006

The atomic coordinates and structure factors (code 2J8P) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by National Institutes of Health Grants GM041752 (to C. M.) and GM64440 (to G. V.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables I and II and Figs. 1 and 2.

¹ Both authors contributed equally to this work.

² Present address: Instituto de Química Física Rocasolano. CSIC, Serrano 119, Madrid 28006, Spain.

³ Present address: Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43221.

⁴ Present address: Dept. of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115.

⁵ To whom correspondence may be addressed: Dept. of Chemistry, University of Washington, Bagley Hall, Seattle, WA 98195-1700. Tel.: 206-543-7113; Fax: 206-685-8665; E-mail: varani{at}chem.washington.edu.

⁶ To whom correspondence may be addressed: Dept. of Molecular Biology and Microbiology, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111. Tel.: 617-636-6935; Fax: 617-636-0337; E-mail: Claire.moore{at}tufts.edu.

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