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J. Biol. Chem., Vol. 283, Issue 20, 14120-14131, May 16, 2008

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Insights into the Mechanism of Progressive RNA Degradation by the Archaeal Exosome^*

Marcos V. A. S. Navarro¹, Carla C. Oliveira, Nilson I. T. Zanchin, and Beatriz G. Guimarães²

From the Brazilian Synchrotron Light Laboratory, 13083-970 Campinas, SP and the Department of Biochemistry, Chemistry Institute, University of São Paulo, 05508-900 São Paulo, SP, Brazil

Initially identified in yeast, the exosome has emerged as a central component of the RNA maturation and degradation machinery both in Archaea and eukaryotes. Here we describe a series of high-resolution structures of the RNase PH ring from the Pyrococcus abyssi exosome, one of them containing three 10-mer RNA strands within the exosome catalytic chamber, and report additional nucleotide interactions involving positions N5 and N7. Residues from all three Rrp41-Rrp42 heterodimers interact with a single RNA molecule, providing evidence for the functional relevance of exosome ring-like assembly in RNA processivity. Furthermore, an ADP-bound structure showed a rearrangement of nucleotide interactions at site N1, suggesting a rationale for the elimination of nucleoside diphosphate after catalysis. In combination with RNA degradation assays performed with mutants of key amino acid residues, the structural data presented here provide support for a model of exosome-mediated RNA degradation that integrates the events involving catalytic cleavage, product elimination, and RNA translocation. Finally, comparisons between the archaeal and human exosome structures provide a possible explanation for the eukaryotic exosome inability to catalyze phosphate-dependent RNA degradation.

Received for publication, February 7, 2008 , and in revised form, March 4, 2008.

The atomic coordinates and structure factors (codes 2PNZ, 2PO0, 2PO1, and 2PO2) 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 Fundação de Amparo à Pesquisa do Estado de São Paulo Grants 05/56493-9 (to C. C. O.), Centro de Pesquisa, Inovacão e Difusão/Centro de Biotecnologia Molecular Estrutural 98/14138-2, and Structural Molecular Biology Network 00/10266-8 (to N. Z. and B. G. G.) and 06/02083-7 (to N. Z.). 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 Figs. S1-S5 and Tables S1 and S2.

¹ To whom correspondence may be addressed: C4-173 Veterinary Medical Center, Cornell University, Ithaca, NY 14853. Fax: 607-253-3659; E-mail: mn372{at}cornell.edu.

² To whom correspondence may be addressed. E-mail: beatriz{at}lnls.br.

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