All-atom simulations disentangle the functional dynamics underlying gene maturation in the intron lariat spliceosome
Lorenzo Casalino, Giulia Palermo, Angelo Spinello, Ursula Rothlisberger, and Alessandra Magistrato
PNAS June 26, 2018. 115 (26) 6584-6589; published ahead of print June 11, 2018. https://doi.org/10.1073/pnas.1802963115
Edited by Michael L. Klein, Temple University, Philadelphia, PA, and approved May 15, 2018 (received for review February 16, 2018)
Significance
Precursor messenger RNA (pre-mRNA) splicing is a crucial step of gene expression, enabling the maturation of pre-mRNA transcripts into protein-coding mRNAs. In humans, a majestic ribonucleoprotein machinery—the spliceosome—governs this fundamental process, the defects and misregulation of which lead to over 200 human diseases. A thorough understanding of splicing is pivotal for biology and medicine, holding the promise of harnessing it for genome modulation applications. Despite the recent breakthroughs gained by cryo-EM, an atomic-resolution picture of the spliceosome functional plasticity is still missing. Here, all-atom simulations elucidate the cooperative motions underlying the functional dynamics of the spliceosome at a late stage of the splicing cycle, suggesting the role of specific proteins involved in the spliceosome disassembly from an atomic-level perspective.
Abstract
The spliceosome (SPL) is a majestic macromolecular machinery composed of five small nuclear RNAs and hundreds of proteins. SPL removes noncoding introns from precursor messenger RNAs (pre-mRNAs) and ligates coding exons, giving rise to functional mRNAs. Building on the first SPL structure solved at near–atomic-level resolution, here we elucidate the functional dynamics of the intron lariat spliceosome (ILS) complex through multi-microsecond-long molecular-dynamics simulations of ∼1,000,000 atoms models. The ILS essential dynamics unveils (i) the leading role of the Spp42 protein, which heads the gene maturation by tuning the motions of distinct SPL components, and (ii) the critical participation of the Cwf19 protein in displacing the intron lariat/U2 branch helix. These findings provide unprecedented details on the SPL functional dynamics, thus contributing to move a step forward toward a thorough understanding of eukaryotic pre-mRNA splicing.
spliceosome splicing molecular dynamics RNA gene maturation
Footnotes
↵1To whom correspondence should be addressed.
Email: alessandra.magistrato@sissa.it.
Author contributions: A.M. designed research; L.C. performed research; L.C., G.P., and A.S. analyzed data; U.R. participated in the discussion of the results; and L.C., G.P., U.R., and A.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1802963115/-/DCSupplementa
Published under the PNAS license.
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