Structural Heterogeneities of the Ribosome: New Frontiers and Opportunities for Cryo-EM

Abstract

The extent of ribosomal heterogeneity has caught increasing interest over the past few years, as recent studies have highlighted the presence of structural variations of the ribosome. More precisely, the heterogeneity of the ribosome covers multiple scales, including the dynamical aspects of ribosomal motion at the single particle level, specialization at the cellular and subcellular scale, or evolutionary differences across species. Upon solving the ribosome atomic structure at medium to high resolution, cryogenic electron microscopy (cryo-EM) has enabled investigating all these forms of heterogeneity. In this review, we present some recent advances in quantifying ribosome heterogeneity, with a focus on the conformational and evolutionary variations of the ribosome and their functional implications. These efforts highlight the need for new computational methods and comparative tools, to comprehensively model the continuous conformational transition pathways of the ribosome, as well as its evolution. While developing these methods presents some important challenges, it also provides an opportunity to extend our interpretation and usage of cryo-EM data, which would more generally benefit the study of molecular dynamics and evolution of proteins and other complexes.

In Ovo Injection of CHIR-99021 Promotes Feather Follicle Development via Modulating the Wnt Signaling Pathway and Transcriptome in Goose Embryos (Anser cygnoides)

“…During the embryonic period in birds, rapid morphogenesis, differentiation, and development of various organs require support from cell division, consisting of quick connection of gene expression programs, acceleration of the translation programs, and quick regulation of protein synthesis ( Guo, 2018 ). During the process, the control of translation is considered the main determining factor of the protein level in the cell, while the ribosome, as the translation machine in protein synthesis plays a central role in the regulation of gene expression ( Bowman, et al, 2020 ; Javed and Orlova, 2019 ; Natchiar, et al, 2015 ; Poitevin, et al, 2020 ). Ribosome and translational control are directly linked with stem cell homeostasis and control of cell fate and play vital roles in the translational regulatory network that controls the identity of stem cells ( Gabut, et al, 2020 ).…”

Ribosomal RNA Pseudouridylation: Will Newly Available Methods Finally Define the Contribution of This Modification to Human Ribosome Plasticity?

“…The use of even more advanced algorithms and software ( Kimanius et al, 2021 ), together with the refinement of the technique itself to achieve higher resolution ( Pellegrino et al, 2022 ), will provide fundamental information on all the ribosomal modifications and detailed interactions in the three-dimensional structure of the native human ribosome. Although some limitations still exist due to the low throughput and time-consuming techniques, cryo-EM will be extremely useful to recognize how particular molecules can bind to specific modified sites in ribosomes and inhibit their activity, offering new insights for structure-based drug design ( Gilles et al, 2020 ; Poitevin et al, 2020 ).…”

Geometric differences in the ribosome exit tunnel impact the escape of small nascent proteins

“…To analyze these complex dynamics, molecular dynamics simulations were previously used [18] to study how the dynamics of the nascent chain are impacted by various biophysical properties of the tunnel, including its geometry [7,[19][20][21], electrostatics [5,22] and 1 hydrophobicity [23]. With the increasing availability of high-resolution structures of the ribosome for various species [24], detailed mappings of the exit tunnel have revealed that these properties can vary across the domains of life [15,19]. Most notable are the geometric differences in tunnel lengths and diameters, as eukaryotic tunnels are, on average, shorter and substantially narrower than prokaryote ones.…”