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. 2015 Jun 11:6:7382.
doi: 10.1038/ncomms8382.

Insights into the origin of the nuclear localization signals in conserved ribosomal proteins

Sergey Melnikov  1 , Adam Ben-Shem  2 , Gulnara Yusupova  2 , Marat Yusupov  3
Affiliations

Insights into the origin of the nuclear localization signals in conserved ribosomal proteins

Sergey Melnikov et al. Nat Commun. .

Abstract

Eukaryotic ribosomal proteins, unlike their bacterial homologues, possess nuclear localization signals (NLSs) to enter the cell nucleus during ribosome assembly. Here we provide a comprehensive comparison of bacterial and eukaryotic ribosomes to show that NLSs appear in conserved ribosomal proteins via remodelling of their RNA-binding domains. This finding enabled us to identify previously unknown NLSs in ribosomal proteins from humans, and suggests that, apart from promoting protein transport, NLSs may facilitate folding of ribosomal RNA.

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Figures

Figure 1
Figure 1. Mapping nuclear/nucleolar localization signals (NLSs) within the ribosome structure reveals their common structural features and provides an insight into their evolutionary origin.
(a) Crystal structures of four pairs of homologous proteins from 70S E. coli and 80S S. cerevisiae ribosomes: proteins are coloured according to the secondary structure, with red colour and red arrows pointing to NLSs of eukaryotic proteins (top panels) and to corresponding positions in bacterial homologues (bottom panels). NLSs reside within non-globular extensions of eukaryotic proteins with substantially remodelled secondary and tertiary structure compared with analogous protein segments in bacterial ribosomal proteins. (b) Fragments of the ribosome interior with a zoom on interactions between NLSs and rRNA within the eukaryotic ribosome (top panels) and corresponding segments of bacterial ribosome structure (bottom panels); nucleotides, which contact ribosomal proteins and ions/water molecules (shown as spheres), are in blue; labels correspond to 23S/25S rRNA helices. When ribosomal proteins are incorporated into the ribosome, NLSs are buried in the rRNA: compared with bacterial ribosomes, NLSs structurally replace non-globular extensions of bacterial proteins or magnesium ions/water in the ribosome interior and form similar stabilizing contacts with single-stranded helical junctions of conserved rRNA, suggesting a role of NLSs in rRNA folding.
Figure 2
Figure 2. Different structure of homologous ribosomal proteins within highly conserved rRNA pockets may point to the location of unknown nuclear localization signals.
Exemplified by identification of NLS in human ribosomal protein uS12. (a) Structure of protein uS12, coloured according to structural conservation: conserved fold is shown in grey and bacteria- and eukaryote-specific in blue and red, respectively; surrounding rRNA is shown schematically with labels indicating 16S/18S rRNA helices. Protein uS12 is one of the 15 ribosomal proteins in which extensions have different folds in bacteria and eukaryotes, despite being bound to nearly identical rRNA cavities of bacterial and eukaryotic ribosomes. (b–h) eGFP fluorescence (top panels) and phase-contrast (bottom panels) snapshots of human cell line HEK293, which express eGFP fusions of human or E. coli protein uS12. Arrows point to nucleoli. All scale bars represent 10 μm. For each sample, eGFP localization was examined in 200 cells. Cells, in which eGFP distribution pattern was common for >95% of the analysed population, were used for imaging. The experiments were replicated three times. (b) eGFP alone (a negative control). (c) Human uS12–eGFP fusion. (d) E. coli uS12–eGFP fusion. (e) A protein hybrid carrying the N terminus of human uS12 and the globular domain of E. coli uS12. (f) A protein hybrid carrying the N terminus of E. coli uS12 and the globular domain of human uS12. (b–h) Identifying NLSs within human uS12 shows that its N-terminal extension (N-H. sapiens) carries NLS activity – by contrast to analogous extension in bacterial uS12 (N-E. coli).
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