By | July 29, 2023

Inside the cell nucleus DNA RNA

New high-resolution images have provided insights into how the large subunit of human ribosomes is assembled, furthering our understanding of these vital cellular machines. The findings, which used cryo-electron microscopy and other techniques, may have implications for studies in cellular metabolism and diseases linked to ribosome mutations.

Life runs on ribosomes. Every cell throughout the world requires ribosomes to convert genetic data into the vital proteins required for the functioning of the organism, and, subsequently, for the production of more ribosomes. But scientists still lack a clear understanding of how these important nanomachines are assembled.

Now, new high-resolution images of the large ribosomal subunit shed light on how nature’s arguably most fundamental molecule comes together in human cells. The findings, published in Sciencebringing us one step closer to a complete picture of ribosome assembly.

“We now have a pretty good idea of ​​how the large ribosomal subunit is assembled in humans,” says The Rockefellers Sebastian Klinge. “We still have a lot of gaps in our understanding, but we certainly now have a much better idea than we had before.”

Solving the large subunit

Ribosomes were first discovered at Rockefeller nearly 70 years ago. Scientists have later determined that they consist of two distinct components: a small 40S subunit responsible for interpreting messengers

RNA
Ribonucleic acid (RNA) is a polymeric molecule similar to DNA that is essential in various biological roles in the coding, decoding, regulation and expression of genes. Both are nucleic acids, but unlike DNA, RNA is single-stranded. An RNA strand has a backbone made of alternating sugar (ribose) and phosphate groups. Attached to each sugar is one of four bases – adenine (A), uracil (U), cytosine (C) or guanine (G). Different types of RNA are found in the cell: messenger RNA (mRNA), ribosomal RNA (rRNA) and transfer RNA (tRNA).

” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>RNAand a larger 60S subunit that links protein fragments. However, those were the broadest strokes. The exact steps by which these complex molecules are assembled into their mature form have long remained a mystery.

Klinge’s approach to this larger problem has long focused on figuring out how ribosomes form in the first place. To that end, Klinge’s lab was among the first to use cryo-electron microscopy to capture images of a non-bacterial ribosome assembling toward its final shape, and the lab has since taken an even more granular approach—carefully piecing together snapshots of mature ribosomes for to understand how these molecules get from one point in their composition to the next.

In recent years, Klinge and other researchers around the world have identified and characterized more than 200 ribosome assembly factors that affect ribosome modification, processing, and folding.

For the current study, Klinge and colleagues focused on the human large ribosomal subunit (60S). The team already knew, from studies in yeast, that the formation of the large subunit involves two precursors (a 5S rRNA and a 32S pre-rRNA) snapping together, but “we wanted to know all the events that have to happen for this to happen,” says Arnaud Vanden Broeck, a postdoctoral researcher in Klinge’s lab. “We wanted to explain how the large subunit is assembled and processed in human cells.”

Vanden Broeck and Klinge combined new techniques involving a mashup of genome editing and biochemistry to capture high-resolution cryo-EM structures of 24 human large ribosomal subunit assembly intermediates as they matured. The resulting images show how assembly factors, various proteins and enzymes, interact with RNA elements to drive the formation and maturation of 60S. Together, the findings represent an almost complete picture of how the human large subunit is assembled.

“For sixty years we had almost nothing on the intermediates that make up the human 60S – it was almost invisible to us – and now we’ve jumped from nothing to pretty good coverage,” says Vanden Broeck, while admitting that some of the rare and most of the transitional steps on the way to the mature 60S may have eluded the team and fallen through the cracks. “We still have a lot to do.”

Nonetheless, important findings from the study may already begin to inform related areas of inquiry. Among the intermediate steps discovered, for example, are signaling pathways that suggest a link between ribosome assembly and cellular metabolism—suggesting that a full understanding of ribosomes may well require close collaboration with experts in cell metabolism. And the granular look at the steps in ribosome formation that the study provides could provide important context for researchers studying diseases linked to ribosome mutations.

For now, however, Klinge and Vanden Broeck are content to marvel at the substantial leap forward. “It’s no more guesswork,” says Klinge. “We can now see in detail what happens when the large subunit is assembled. It is humbling to realize that we can finally see what makes ribosomes and drives protein formation in all our own cells.”

Reference: “Principles of human pre-60S biogenesis” by Arnaud Vanden Broeck and Sebastian Klinge, 7 July 2023, Science.
DOI: 10.1126/science.adh3892


#research #sheds #light #formation #natures #fundamental #molecules

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