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Tezpur University (TU), Tezpur
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RNA Mimicry by the Fap7 Adenylate Kinase in Ribosome Biogenesis ro me Loc h1., Magali Blaud1., Ste phane Re ty1, Simon Lebaron1,2, Patrick Deschamps1, Je 1 1 Joseph Bareille , Julie Jombart , Julien Robert-Paganin1, Lila Delbos1, Florian Chardon1, Elodie Zhang1, ment Charenton1, David Tollervey2, Nicolas Leulliot1* Cle Paris Descartes, Faculte de Pharmacie, Sorbonne Paris Cite , Paris, France, 2 Wellcome 1 Laboratoire de Cristallographie et RMN Biologiques, UMR CNRS 8015, Universite Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, Scotland Abstract During biogenesis of the 40S and 60S ribosomal subunits, the pre-40S particles are exported to the cytoplasm prior to final cleavage of the 20S pre-rRNA to mature 18S rRNA. Amongst the factors involved in this maturation step, Fap7 is unusual, as it both interacts with ribosomal protein Rps14 and harbors adenylate kinase activity, a function not usually associated with ribonucleoprotein assembly. Human hFap7 also regulates Cajal body assembly and cell cycle progression via the p53 MDM2 pathway. This work presents the functional and structural characterization of the Fap7 Rps14 complex. We report that Fap7 association blocks the RNA binding surface of Rps14 and, conversely, Rps14 binding inhibits adenylate kinase activity of Fap7. In addition, the affinity of Fap7 for Rps14 is higher with bound ADP, whereas ATP hydrolysis dissociates the complex. These results suggest that Fap7 chaperones Rps14 assembly into pre-40S particles via RNA mimicry in an ATPdependent manner. Incorporation of Rps14 by Fap7 leads to a structural rearrangement of the platform domain necessary for the pre-rRNA to acquire a cleavage competent conformation. ty S, Lebaron S, Deschamps P, et al. (2014) RNA Mimicry by the Fap7 Adenylate Kinase in Ribosome Biogenesis. PLoS Biol 12(5): Citation: Loc h J, Blaud M, Re e1001860. doi:10.1371/journal.pbio.1001860 Academic Editor: Gregory A. Petsko, Brandeis University, United States of America Received August 13, 2013; Accepted April 4, 2014; Published May 13, 2014 Copyright: 2014 Loc h et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Work at UPD was supported by CNRS, University Paris Descartes, the RNPGenesis grant from the Agence Nationale de la Recherche (ANR JC), the Institut Universitaire de France (to NL), and The Foundation Descartes (to JJ). SL and DT were supported by the Wellcome Trust (077248). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Abbreviations: ADP, adenosine di-phosphate; AK, adenylate kinase; AMP, adenosine mono-phosphate; AMPK, AMP-activated protein kinase; Ap5A, diadenosine pentaphosphate; ATP, adenosine nucleotide triphosphate; DTT, Dithiothreitol; IMAC, metal ion affinity chromatography; LDH, lactate dehydrogenase; PEP, Phospho(enol)pyruvate; PK, pyruvate kinase; Rg, radius of gyration; r.m.s.d., root mean square deviation; RNP, ribonucleoprotein; RT, room temperature; SAXS, small angle X-ray scattering; SDS-PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis; snRNP, small nuclear ribonucleoprotein. * E-mail: nicolas.leulliot@parisdescartes.fr . These authors contributed equally to this work. structural homology to adenylate kinases (AKs) and harbors a broad AK activity [11,12]. AKs catalyze the reversible transfer of the c phosphate of adenosine nucleotide triphosphate (ATP) to an adenosine mono-phosphate (AMP), forming two molecules of adenosine di-phosphate (ADP). AKs play important roles in nucleotide metabolism [13], but the link between this enzymatic activity and ribonucleoprotein (RNP) assembly is enigmatic. In yeast, yFap7 is necessary for the late cytoplasmic maturation steps of the 40S particle, and strictly required for the cleavage at site D [5,14]. However, the association of yFap7 with the pre-40S particles is either weak or very transient [5,14]. In the absence of yFap7, pre-40S subunits accumulate in 80S-like particles, containing 20S pre-rRNA. An active site mutant in yFap7 has the same phenotype, demonstrating a requirement for AK activity [5,14]. The catalytic activity of hFap7 is also important in the assembly and/or stability of Cajal bodies [12,15,16], nuclear domains involved in the maturation of small nuclear RNP (snRNP) particles [17]. Fap7 forms a complex with Rps14 that is conserved between humans, yeast, and archea [14,18,19]. Rps14 is a component of the platform domain of the small subunit, and its C terminus forms Introduction Over 200 preribosomal factors are involved in the maturation of ribosomes. Most of these factors are essential for cell survival, but their precise molecular functions remain elusive (for reviews, see [1 3]). One of the last steps of maturation of the small subunit of the ribosome is the cytoplasmic cleavage of the 20S pre-rRNA at site D to generate 18S rRNA. This cleavage is carried out by the endonuclease Nob1 in 80S-like complexes composed of pre-40S particles and mature 60S [4,5]. Cleavage also requires multiple pre-40S factors including the Nob1 binding protein Pno1/Dim2, the methyltransferase Dim1, the export factors Enp1 and Ltv1, and several NTPases including the Rio1 and Rio2 protein kinases, the Prp43 helicase and its cofactor Pfa1, the GTPase-related factor Tsr1, and the Fap7 NTPase. The locations of maturation factors in the late pre-40S particles is emerging from in vivo RNA binding (CRAC), cryo-EM, and crystallographic studies on preribosomal particles [6 10], but detailed understanding of their functions remains limited. Amongst late pre-40S factors, the function of Fap7 is especially intriguing. Human hFap7 (also called hCINAP or AK6) bears PLOS Biology | www.plosbiology.org 1 May 2014 | Volume 12 | Issue 5 | e1001860

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