New research sheds light on the formation of one of nature’s most fundamental molecules

New high-resolution images have provided insights into how a large subset of human ribosomes assemble, improving our understanding of these essential cellular machines. The findings, using cryo-electron microscopy and other techniques, may have implications for studies of cellular metabolism and diseases associated with ribosome mutations.

Life runs on ribosomes. Every cell around the world needs ribosomes to convert genetic data into essential proteins necessary for the organism to function. However, scientists still lack a clear understanding of how these essential nanomachines are assembled.

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

„We now have a good idea of ​​how the large ribosomal subunit is assembled in humans,” says Rockefeller’s Sebastian Klinge. „There are still some gaps in our understanding, but we certainly have a better idea now than we had before.”

Solving the Large Subset

Ribosomes were first discovered 70 years ago by Rockefeller. Researchers have since established that it consists of two separate components: a small 40S subunit responsible for signaling the messenger; RNA, and the large 60S subunit that binds protein fragments. However, they are very broad strokes. The precise steps by which these complex molecules are assembled into their mature form have long remained a mystery.

Kling’s approach to this big problem has long focused on figuring out how ribosomes form in the first place. To that end, Kling’s lab was the first to use cryo-electron microscopy to capture views of a non-bacterial ribosome moving toward its final form, and the lab took an even more nuanced approach—stitching together snapshots of maturing ribosomes. Understand how these molecules move from one phase to the next.

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

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 binds two precursors (5S rRNA and 32S pre-rRNA) together, but „we wanted to know all the events that require this to occur,” says Arnott Vanden Broeck, a postdoctoral researcher in Kling’s lab. We wanted to explain how it is assembled and processed in cells.”

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

„For sixty years we’ve had nothing on the intermediates that make up human 60S—they’re all invisible to us—and now we’ve progressed from nothing to good coverage,” Vanden Broeck says, admitting that some are rare. And very unstable steps in the mature 60S pathway may have fallen through the cracks, bypassing the matrix. „We still have a lot of work to do.”

Nevertheless, key findings from the study can already begin to inform related fields of inquiry. For example, among the intermediate steps discovered are signaling pathways that suggest a link between ribosome assembly and cellular metabolism—suggesting that a complete understanding of ribosomes may require close collaboration with experts in cell metabolism. The granular view of the steps in ribosome formation provided by the study may provide important context for scientists studying diseases linked to ribosome mutations.

For now, though, Klinge and Vanden Broeck are content to marvel at the considerable leap forward. „It’s no longer guesswork,” Klinge says. „We can now see in detail what happens when the large subunit comes together. It’s humbling to realize that we can finally see what makes ribosomes and what drives protein formation in all of our own cells.

Reference: Arnott Vanden Broeck and Sebastian Klinge, “Theories of Human Biogenesis before the 60S”, 7 July 2023. Science.
DOI: 10.1126/science.adh3892

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