English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

The removal of non-coding introns within a precursor messenger RNA (pre-mRNA) transcript is a key step of gene expression and regulation, occurring via two transesterification reactions mediated by at least two Mg2+ ions (Kastner et al., 2019). Whereas in lower organisms this process is self-regulated by group II intron ribozymes (G2IRs) performing their own excision from a pre-mRNA strand, in eukaryotes, due to the increased complexity of the genome, these autocatalytic RNAs have evolved into a majestic protein/RNA machinery—the spliceosome (SPL)—composed of hundreds of proteins and five small-nuclear (sn)RNA filaments (Marcia and Pyle, 2012; Yan et al., 2019). The SPL, acting as a protein-directed metallo-ribozyme, promotes the conversion of pre-mRNAs into mature mRNAs. This massive architecture revolves around its central core constituted by Spp42/Prp8 protein (S. Pombe/S. Cerevisiae or human, respectively) and a catalytic site fully resembling that of G2IRs (Yan et al., 2019). As the most eminent genome tailor, the SPL undergoes a relentless compositional and conformational remodeling, repetitively assembling and transforming at every splicing cycle into eight distinct complexes (A, B, Bact, B, C, C, P, ILS) to achieve splicing with a single nucleotide precision. Recent developments in single-particle cryo-EM have led to elucidate a plethora of near-atomic resolution structures of SPL complexes from human and yeast strains, thus allowing decades of biochemical, structural and functional studies to be interpreted. In this context, multiscale simulations can contribute to deciphering the intricacies of the splicing mechanism by assessing the chemical details of the pre-mRNA cleavage, and the role of the extraordinarily convoluted protein/RNA environment in creating the appropriate structural scaffold that finely modulates introns removal (Yan et al., 2019). Nevertheless, the size and the inner complexity of the SPL machinery require a wise use of advanced multiscale simulations to tackle the many different peculiarities of its mechanism, as shown in the following showcased studies.

Unraveling the Molecular Mechanism of Pre-mRNA Splicing From Multi-Scale Simulations