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Ribosome customization and functional diversification amongst P-stalk proteins regulate late poxvirus protein synthesis

ABSTRACT: Growing evidence suggests that ribosomes selectively regulate translation of specific mRNA subsets. Here, quantitative proteomics and cryo-electron microscopy demonstrated that poxvirus infection does not alter ribosomal subunit protein (RP) composition but skews 40S rotation states and displaces the 40S head domain. Genetic knockout screens employing metabolic assays and a dual-reporter virus further identified two RPs that selectively regulate non-canonical translation of late poxvirus mRNAs which contain unusual 5 polyA-leaders: RACK1 and RPLP2. RACK1 is a component of the altered 40S head domain while RPLP2 is a subunit of the P-stalk, wherein RPLP0 anchors two heterodimers of RPLP1 and RPLP2 to the large 60S subunit. RPLP0 was required for global translation, yet RPLP1 was dispensable while RPLP2 was specifically required for non-canonical poxvirus protein synthesis. Combined, we demonstrate that poxviruses structurally customize ribosomes and become reliant upon traditionally non-essential RPs from both ribosomal subunits for efficient initiation on their late mRNAs.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Vaccinia Virus Western Reserve (ncbitaxon:696871) Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Derek Walsh

PROVIDER: MSV000096224 | MassIVE | Fri Oct 25 13:07:00 BST 2024

REPOSITORIES: MassIVE

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Project description:Firczuk2013 - Eukaryotic mRNA translation machinery This is a model of Saccharomyces cerevisiae mRNA translation which includes the initiation, elongation and termination phases. The model is for 20 condon mRNAs. The building of a multi-factor complex in initiation and also the different processes in elongation and termination are modelled in detail. The model takes into account that ribosomes cover more than one codon of mRNA so that the movement of ribosomes are effectively blocked by other ribosomes several codons downstream. It is assumed that 15 codons are occupied by each ribosome. This blocking effect is considered in reaction R18 in initiation and also reaction R26, the reaction where translocation of ribosomes takes place in elongation. The kinetic functions of these two reactions are based on MacDonald et al. 1968 and Heinrich & Rapaport 1980. All other kinetic functions follow mass-action kinetics. The concentrations of transfer RNA species (Met-tRNA, aa-tRNA and tRNA in the model) are kept constant, while the other species' concentrations can change in the course of the simulation. The model describes the translation of a short mRNA with 20 codons. Therefore, all reactions in the elongation cycle (R22, R23, R25, R26, R28 and R29) and the corresponding species are replicated accordingly to model the species with ribosomes bound at different positions. In summary, the model contains 165 different species and 141 reactions. The value of the 56 rate constant parameters were estimated by fitting the model against a series of experimental data consisting of modulation of the various translation factors (Figures 2, 3 and S3). Overall the parameter estimation was carried out over 212 different data points (steady states). This model is described in the article: An in vivo control map for the eukaryotic mRNA translation machinery Helena Firczuk, Shichina Kannambath, Jürgen Pahle, Amy Claydon, Robert Beynon, John Duncan, Hans Westerhoff, Pedro Mendes and John EG McCarthy Molecular Systems Biology. 9:635 Abstract: Rate control analysis defines the in vivo control map governing yeast protein synthesis and generates an extensively parameterized digital model of the translation pathway. Among other non-intuitive outcomes, translation demonstrates a high degree of functional modularity and comprises a non-stoichiometric combination of proteins manifesting functional convergence on a shared maximal translation rate. In exponentially growing cells, polypeptide elongation (eEF1A, eEF2, and eEF3) exerts the strongest control. The two other strong control points are recruitment of mRNA and tRNAi to the 40S ribosomal subunit (eIF4F and eIF2) and termination (eRF1; Dbp5). In contrast, factors that are found to promote mRNA scanning efficiency on a longer than-average 5′untranslated region (eIF1, eIF1A, Ded1, eIF2B, eIF3, and eIF5) exceed the levels required for maximal control. This is expected to allow the cell to minimize scanning transition times, particularly for longer 5′UTRs. The analysis reveals these and other collective adaptations of control shared across the factors, as well as features that reflect functional modularity and system robustness. Remarkably, gene duplication is implicated in the fine control of cellular protein synthesis. This model is hosted on BioModels Database and identified by: BIOMD0000000457 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Ribosome customization and functional diversification amongst P-stalk proteins regulate late poxvirus protein synthesis

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