bims-tricox Biomed News
on Translation, ribosomes and COX
Issue of 2024–12–29
three papers selected by
Yash Verma, University of Zurich
  1. Structural determinants of co-translational protein complex assembly.
  2. The Vsr-like protein FASTKD4 regulates the stability and polyadenylation of the MT-ND3 mRNA.
  3. Formyl-methionine-mediated eukaryotic ribosome quality control pathway for cold adaptation.
  1. Cell. 2024 Dec 18. pii: S0092-8674(24)01330-8. [Epub ahead of print]
    Structural determinants of co-translational protein complex assembly.
    Saurav Mallik, Johannes Venezian, Arseniy Lobov, Meta Heidenreich, Hector Garcia-Seisdedos, Todd O Yeates, Ayala Shiber, Emmanuel D Levy.
      Protein assembly into functional complexes is critical to life's processes. While complex assembly is classically described as occurring between fully synthesized proteins, recent work showed that co-translational assembly is prevalent in human cells. However, the biological basis for the existence of this process and the identity of protein pairs that assemble co-translationally remain unknown. We show that co-translational assembly is governed by structural characteristics of complexes and involves mutually stabilized subunits. Accordingly, co-translationally assembling subunits are unstable in isolation and exhibit synchronized proteostasis with their partner. By leveraging structural signatures and AlphaFold2-based predictions, we accurately predicted co-translational assembly, including pair identities, at proteome scale and across species. We validated our predictions by ribosome profiling, stoichiometry perturbations, and single-molecule RNA-fluorescence in situ hybridization (smFISH) experiments that revealed co-localized mRNAs. This work establishes a fundamental connection between protein structure and the translation process, highlighting the overarching impact of three-dimensional structure on gene expression, mRNA localization, and proteostasis.
    Keywords:  AlphaFold; co-translational assembly; mRNA localization; protein complexes; protein interactions; protein structure; proteostasis; ribosome profiling; single-molecule FISH; translational regulation
    DOI:  https://doi.org/10.1016/j.cell.2024.11.013
  2. Nucleic Acids Res. 2024 Dec 27. pii: gkae1261. [Epub ahead of print]
    The Vsr-like protein FASTKD4 regulates the stability and polyadenylation of the MT-ND3 mRNA.
    Xuan Yang, Maike Stentenbach, Laetitia A Hughes, Stefan J Siira, Kelvin Lau, Michael Hothorn, Jean-Claude Martinou, Oliver Rackham, Aleksandra Filipovska.
      Expression of the compact mitochondrial genome is regulated by nuclear encoded, mitochondrially localized RNA-binding proteins (RBPs). RBPs regulate the lifecycles of mitochondrial RNAs from transcription to degradation by mediating RNA processing, maturation, stability and translation. The Fas-activated serine/threonine kinase (FASTK) family of RBPs has been shown to regulate and fine-tune discrete aspects of mitochondrial gene expression. Although the roles of specific targets of FASTK proteins have been elucidated, the molecular mechanisms of FASTK proteins in mitochondrial RNA metabolism remain unclear. Therefore, we resolved the structure of FASTKD4 at atomic level that includes the RAP domain and the two FAST motifs, creating a positively charged cavity resembling that of the very short patch repair endonuclease. Our biochemical studies show that FASTKD4 binds the canonical poly(A) tail of MT-ND3 enabling its maturation and translation. The in vitro role of FASTKD4 is consistent with its loss in cells that results in decreased MT-ND3 polyadenylation, which destabilizes this messenger RNA in mitochondria.
    DOI:  https://doi.org/10.1093/nar/gkae1261
  3. Mol Cell. 2024 Dec 17. pii: S1097-2765(24)00990-0. [Epub ahead of print]
    Formyl-methionine-mediated eukaryotic ribosome quality control pathway for cold adaptation.
    Chang-Seok Lee, Jaehwan Sim, Sang-Yoon Kim, Hyeonji Lee, Tae-Young Roh, Cheol-Sang Hwang.
      Protein synthesis in the eukaryotic cytosol can start using both conventional methionine and formyl-methionine (fMet). However, a mechanism, if such exists, for detecting and regulating the incorporation of fMet (instead of Met) during translation, thereby preventing cellular toxicity of nascent fMet-bearing (fMet-) polypeptides, remains unknown. Here, we describe the fMet-mediated ribosome quality control (fMet-RQC) pathway in Saccharomyces cerevisiae. A eukaryotic translation initiation factor 3 subunit c, Nip1, specifically recognizes N-terminal fMet in nascent polypeptides, recruiting a small GTPase, Arf1, to induce ribosome stalling, largely with 41-residue fMet-peptidyl tRNAs. This leads to ribosome dissociation and subsequent stress granule formation. Loss of the fMet-RQC pathway causes the continued synthesis of fMet polypeptides, which inhibits essential N-terminal Met modifications and promotes their coaggregation with ribosomes. This fMet-RQC pathway is important for the adaptation of yeast cells to cold stress by promoting stress granule formation and preventing a buildup of toxic fMet polypeptides.
    Keywords:  Arf1; Nip1; cellular adaptation; cold stress; formyl-methionine; proteotoxicity; ribosome quality control; stress granule
    DOI:  https://doi.org/10.1016/j.molcel.2024.11.035
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