Genome complexity: spliceosome molecules in action (Introduction)

by David Turell , Friday, December 18, 2020, 22:49 (1223 days ago) @ David Turell

Extreme complexity of specialized molecules:

https://science.sciencemag.org/content/370/6523/eabc3753

"Abstract
Spliceosome activation involves extensive protein and RNA rearrangements that lead to formation of a catalytically active U2/U6 RNA structure. At present, little is known about the assembly pathway of the latter and the mechanism whereby proteins aid its proper folding. Here, we report the cryo–electron microscopy structures of two human, activated spliceosome precursors (that is, pre-Bact complexes) at core resolutions of 3.9 and 4.2 angstroms. These structures elucidate the order of the numerous protein exchanges that occur during activation, the mutually exclusive interactions that ensure the correct order of ribonucleoprotein rearrangements needed to form the U2/U6 catalytic RNA, and the stepwise folding pathway of the latter. Structural comparisons with mature Bact complexes reveal the molecular mechanism whereby a conformational change in the scaffold protein PRP8 facilitates final three-dimensional folding of the U2/U6 catalytic RNA."

***

"Conclusions
The human pre-Bact structures presented here reveal that there is an intricate cascade of highly coordinated structural changes during the activation phase of the human spliceosome, involving mutually exclusive protein-protein and protein-RNA interactions that facilitate the directionality of the activation process. One unexpected finding of our studies was that the conformational change in PRP8 leading to its closed conformation first occurs during the late stages of activation. An open PRP8 conformation would be important to allow space for the initial stepwise rearrangements in the U2 and U6 snRNAs that lead to the U6 ISL and U2/U6 helix Ib and to accommodate KIN17 in pre-Bact-2 and WBP11, which appears to stabilize and/or position the U6 ISL in pre-Bact-1. Our studies show that the folding of the native 3D structure of the U2/U6 active site proceeds as follows. First, key U2/U6 secondary structural elements are sequentially formed and, together with a large number of proteins—including CDC5L, PLRG1, SYF3, SKIP, and CWC15—they are anchored and/or positioned on the central PRP8 scaffold while in its open B complex conformation. Second, during PRP8’s subsequent conformational change, the U2/U6 RNA elements that are docked to the Large domain are moved toward the U6 ISL. Concomitantly, all proteins docked to the PRP8 Large domain are also repositioned, thereby restricting the space in the closed PRP8 cavity. In this manner a proteinaceous folding chamber or mold is generated that aids U2/U6 helix Ia formation and the final tertiary folding of the active site RNA. Thus, the cryo-EM structures of two human pre-Bact complexes presented here allow new insights into the strategy used by the spliceosome to assemble its catalytic RNA network and how a conformational rearrangement in PRP8 facilitates the 3D folding of the catalytically active U2/U6 RNA."

Comment: Look at the models of the machinery. Design cannot be denied. The orchestrated opening and folded of orchestrated molecules in concert reeks of mental design.