-
The Journal of Biological Chemistry 2021This essay, which was written to commemorate the 50th anniversary of the Protein Data Bank, opens with some comments about the intentions of the scientists who pressed... (Review)
Review
This essay, which was written to commemorate the 50th anniversary of the Protein Data Bank, opens with some comments about the intentions of the scientists who pressed for its establishment and the nature of services it provides. It includes a brief account of the events that resulted in the determination of the crystal structure of the large ribosomal subunit from Haloarcula marismortui. The magnitude of the challenge the first ribosome crystal structures posed for the PDB is commented upon, and in the description of subsequent developments in the ribosome structure field that follows, it is pointed out that cryo-EM has replaced X-ray crystallography as the method of choice for investigating ribosome structure.
Topics: Cryoelectron Microscopy; Crystallography, X-Ray; Databases, Protein; Nuclear Magnetic Resonance, Biomolecular; Protein Conformation; Proteins; Ribosomes
PubMed: 33744288
DOI: 10.1016/j.jbc.2021.100561 -
Cell Stem Cell Jul 2021Impaired ribosome function is the underlying etiology in a group of bone marrow failure syndromes called ribosomopathies. However, how ribosomes are regulated remains...
Impaired ribosome function is the underlying etiology in a group of bone marrow failure syndromes called ribosomopathies. However, how ribosomes are regulated remains poorly understood, as are approaches to restore hematopoietic stem cell (HSC) function loss because of defective ribosome biogenesis. Here we reveal a role of the E3 ubiquitin ligase HectD1 in regulating HSC function via ribosome assembly and protein translation. Hectd1-deficient HSCs exhibit a striking defect in transplantation ability and ex vivo maintenance concomitant with reduced protein synthesis and growth rate under stress conditions. Mechanistically, HectD1 ubiquitinates and degrades ZNF622, an assembly factor for the ribosomal 60S subunit. Hectd1 loss leads to accumulation of ZNF622 and the anti-association factor eIF6 on 60S, resulting in 60S/40S joining defects. Importantly, Znf622 depletion in Hectd1-deficient HSCs restored ribosomal subunit joining, protein synthesis, and HSC reconstitution capacity. These findings highlight the importance of ubiquitin-coordinated ribosome assembly in HSC regeneration.
Topics: Hematopoietic Stem Cells; Protein Biosynthesis; Ribosomes
PubMed: 33711283
DOI: 10.1016/j.stem.2021.02.008 -
Current Opinion in Rheumatology Jan 2022Translation of genetic information encoded within mRNA molecules by ribosomes into proteins is a key part of the central dogma of molecular biology. Despite the central... (Review)
Review
PURPOSE OF REVIEW
Translation of genetic information encoded within mRNA molecules by ribosomes into proteins is a key part of the central dogma of molecular biology. Despite the central position of the ribosome in the translation of proteins, and considering the major proteomic changes that occur in the joint during osteoarthritis development and progression, the ribosome has received very limited attention as driver of osteoarthritis pathogenesis.
RECENT FINDINGS
We provide an overview of the limited literature regarding this developing topic for the osteoarthritis field. Recent key findings that connect ribosome biogenesis and activity with osteoarthritis include: ribosomal RNA transcription, processing and maturation, ribosomal protein expression, protein translation capacity and preferential translation.
SUMMARY
The ribosome as the central cellular protein synthesis hub is largely neglected in osteoarthritis research. Findings included in this review reveal that in osteoarthritis, ribosome aberrations have been found from early-stage ribosome biogenesis, through ribosome build-up and maturation, up to preferential translation. Classically, osteoarthritis has been explained as an imbalance between joint tissue anabolism and catabolism. We postulate that osteoarthritis can be interpreted as an acquired ribosomopathy. This hypothesis fine-tunes the dogmatic anabolism/katabolism point-of-view, and may provide novel molecular opportunities for the development of osteoarthritis disease-modifying treatments.
Topics: Humans; Osteoarthritis; Proteomics; RNA, Ribosomal; Ribosomal Proteins; Ribosomes
PubMed: 34750309
DOI: 10.1097/BOR.0000000000000858 -
Annual Review of Biochemistry Jun 2022Accurate protein synthesis (translation) relies on translation factors that rectify ribosome fluctuations into a unidirectional process. Understanding this process... (Review)
Review
Accurate protein synthesis (translation) relies on translation factors that rectify ribosome fluctuations into a unidirectional process. Understanding this process requires structural characterization of the ribosome and translation-factor dynamics. In the 2000s, crystallographic studies determined high-resolution structures of ribosomes stalled with translation factors, providing a starting point for visualizing translation. Recent progress in single-particle cryogenic electron microscopy (cryo-EM) has enabled near-atomic resolution of numerous structures sampled in heterogeneous complexes (ensembles). Ensemble and time-resolved cryo-EM have now revealed unprecedented views of ribosome transitions in the three principal stages of translation: initiation, elongation, and termination. This review focuses on how translation factors help achieve high accuracy and efficiency of translation by monitoring distinct ribosome conformations and by differentially shifting the equilibria of ribosome rearrangements for cognate and near-cognate substrates.
Topics: Cryoelectron Microscopy; Ribosomes; Single Molecule Imaging
PubMed: 35287473
DOI: 10.1146/annurev-biochem-071921-122857 -
Biochemistry Nov 2019As the influence of translation rates on protein folding and function has come to light, the mechanisms by which translation speed is modulated have become an important... (Review)
Review
As the influence of translation rates on protein folding and function has come to light, the mechanisms by which translation speed is modulated have become an important issue. One mechanism entails the generation of force by the nascent protein. Cotranslational processes, such as nascent protein folding, the emergence of unfolded nascent chain segments from the ribosome's exit tunnel, and insertion of the nascent chain into or translocation of the nascent chain through membranes, can generate forces that are transmitted back to the peptidyl transferase center and affect translation rates. In this Perspective, we examine the processes that generate these forces, the mechanisms of transmission along the ribosomal exit tunnel to the peptidyl transferase center, and the effects of force on the ribosome's catalytic cycle. We also discuss the physical models that have been developed to predict and explain force generation for individual processes and speculate about other processes that may generate forces that have yet to be tested.
Topics: Animals; Biomechanical Phenomena; Humans; Kinetics; Models, Molecular; Peptidyl Transferases; Protein Biosynthesis; Ribosomes
PubMed: 31134795
DOI: 10.1021/acs.biochem.9b00260 -
Cells Oct 2019Subverting the conventional concept of "the" ribosome, a wealth of information gleaned from recent studies is revealing a much more diverse and dynamic ribosomal reality... (Review)
Review
Subverting the conventional concept of "the" ribosome, a wealth of information gleaned from recent studies is revealing a much more diverse and dynamic ribosomal reality than has traditionally been thought possible. A diverse array of researchers is collectively illuminating a universe of heterogeneous and adaptable ribosomes harboring differences in composition and regulatory capacity: These differences enable specialization. The expanding universe of ribosomes not only comprises an incredible richness in ribosomal specialization between species, but also within the same tissues and even cells. In this review, we discuss ribosomal heterogeneity and speculate how the emerging understanding of the ribosomal repertoire is impacting the biological sciences today. Targeting pathogen-specific and pathological "diseased" ribosomes promises to provide new treatment options for patients, and potential applications for "designer ribosomes" are within reach. Our deepening understanding of and ability to manipulate the ribosome are establishing both the technological and theoretical foundations for major advances for the 21 century and beyond.
Topics: Animals; Humans; Ribosomes; Species Specificity
PubMed: 31590378
DOI: 10.3390/cells8101205 -
Methods in Molecular Biology (Clifton,... 2022Protein synthesis in eukaryotes is carried out by 80S ribosomes with the help of many specific translation factors. Translation comprises four major steps: initiation,... (Review)
Review
Protein synthesis in eukaryotes is carried out by 80S ribosomes with the help of many specific translation factors. Translation comprises four major steps: initiation, elongation, termination, and ribosome recycling. In this review, we provide a comprehensive list of translation factors required for protein synthesis in yeast and higher eukaryotes and summarize the mechanisms of each individual phase of eukaryotic translation.
Topics: Protein Biosynthesis; Ribosomes; Saccharomyces cerevisiae
PubMed: 35796991
DOI: 10.1007/978-1-0716-2501-9_13 -
Biochemistry. Biokhimiia Aug 2021During protein synthesis, ribosome moves along mRNA to decode one codon after the other. Ribosome translocation is induced by a universally conserved protein, elongation... (Review)
Review
During protein synthesis, ribosome moves along mRNA to decode one codon after the other. Ribosome translocation is induced by a universally conserved protein, elongation factor G (EF-G) in bacteria and elongation factor 2 (EF-2) in eukaryotes. EF-G-induced translocation results in unwinding of the intramolecular secondary structures of mRNA by three base pairs at a time that renders the translating ribosome a processive helicase. Professor Alexander Sergeevich Spirin has made numerous seminal contributions to understanding the molecular mechanism of translocation. Here, we review Spirin's insights into the ribosomal translocation and recent advances in the field that stemmed from Spirin's pioneering work. We also discuss key remaining challenges in studies of translocase and helicase activities of the ribosome.
Topics: Biological Transport; Cryoelectron Microscopy; Eukaryota; Fluorescence Resonance Energy Transfer; Models, Molecular; Peptide Elongation Factor 2; Peptide Elongation Factor G; Protein Biosynthesis; RNA Helicases; RNA, Messenger; RNA, Transfer; Ribosomes; Transferases
PubMed: 34488575
DOI: 10.1134/S0006297921080095 -
Wiley Interdisciplinary Reviews. RNA Jul 2021Regulation of protein synthesis is a vital step in controlling gene expression, especially during development. Over the last 10 years, it has become clear that rather... (Review)
Review
Regulation of protein synthesis is a vital step in controlling gene expression, especially during development. Over the last 10 years, it has become clear that rather than being homogeneous machines responsible for mRNA translation, ribosomes are highly heterogeneous and can play an active part in translational regulation. These "specialized ribosomes" comprise of specific protein and/or rRNA components, which are required for the translation of particular mRNAs. However, while there is extensive evidence for ribosome heterogeneity, support for specialized functions is limited. Recent work in a variety of developmental model organisms has shed some light on the biological relevance of ribosome heterogeneity. Tissue-specific expression of ribosomal components along with phenotypic analysis of ribosomal gene mutations indicate that ribosome heterogeneity and potentially specialization are common in key development processes like embryogenesis, spermatogenesis, oogenesis, body patterning, and neurogenesis. Several examples of ribosome specialization have now been proposed but strong links between ribosome heterogeneity, translation of specific mRNAs by defined mechanisms, and role of these translation events remain elusive. Furthermore, several studies have indicated that heterogeneous ribosome populations are a product of tissue-specific expression rather than specialized function and that ribosomal protein phenotypes are the result of extra-ribosomal function or overall reduced ribosome levels. Many important questions still need to be addressed in order to determine the functional importance of ribosome heterogeneity to development and disease, which is likely to vary across systems. It will be essential to dissect these issues to fully understand diseases caused by disruptions to ribosomal composition, such as ribosomopathies. This article is categorized under: Translation > Translation Regulation Translation > Ribosome Structure/Function RNA in Disease and Development > RNA in Development.
Topics: Gene Expression Regulation, Developmental; Protein Biosynthesis; RNA, Messenger; RNA, Ribosomal; Ribosomal Proteins; Ribosomes
PubMed: 33565275
DOI: 10.1002/wrna.1644 -
Nucleic Acids Research Feb 2020During canonical translation, the ribosome moves along an mRNA from the start to the stop codon in exact steps of one codon at a time. The collinearity of the mRNA and... (Review)
Review
During canonical translation, the ribosome moves along an mRNA from the start to the stop codon in exact steps of one codon at a time. The collinearity of the mRNA and the protein sequence is essential for the quality of the cellular proteome. Spontaneous errors in decoding or translocation are rare and result in a deficient protein. However, dedicated recoding signals in the mRNA can reprogram the ribosome to read the message in alternative ways. This review summarizes the recent advances in understanding the mechanisms of three types of recoding events: stop-codon readthrough, -1 ribosome frameshifting and translational bypassing. Recoding events provide insights into alternative modes of ribosome dynamics that are potentially applicable to other non-canonical modes of prokaryotic and eukaryotic translation.
Topics: Codon, Terminator; Frameshifting, Ribosomal; Protein Biosynthesis; Ribosomes
PubMed: 31511883
DOI: 10.1093/nar/gkz783