Mechanism of completion of peptidyltransferase centre assembly in eukaryotes

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From: eLife(Vol. 8)
Publisher: eLife Science Publications, Ltd.
Document Type: Report
Length: 17,794 words
Lexile Measure: 1490L

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Abstract :

During their final maturation in the cytoplasm, pre-60S ribosomal particles are converted to translation-competent large ribosomal subunits. Here, we present the mechanism of peptidyltransferase centre (PTC) completion that explains how integration of the last ribosomal proteins is coupled to release of the nuclear export adaptor Nmd3. Single-particle cryo-EM reveals that eL40 recruitment stabilises helix 89 to form the uL16 binding site. The loading of uL16 unhooks helix 38 from Nmd3 to adopt its mature conformation. In turn, partial retraction of the L1 stalk is coupled to a conformational switch in Nmd3 that allows the uL16 P-site loop to fully accommodate into the PTC where it competes with Nmd3 for an overlapping binding site (base A2971). Our data reveal how the central functional site of the ribosome is sculpted and suggest how the formation of translation-competent 60S subunits is disrupted in leukaemia-associated ribosomopathies. eLife digest Biological machines called ribosomes make proteins in the cells of our body. Mammalian cells build roughly 7,500 new ribosomes every minute, each one containing 80 proteins and four RNA molecules. Problems that prevent ribosomes from assembling correctly have been linked to cancers such as leukemia, and a class of disorders called ribosomopathies that increase the likelihood of someone developing cancer. Understanding how ribosomes assemble could therefore help to develop new treatments for these diseases. Ribosomes are mostly constructed in the cell nucleus, but the final stages of assembly occur in the cytoplasm of the cell. A protein called Nmd3 binds to the partly constructed ribosome to export it out of the nucleus. Then, the final ribosomal proteins integrate into the structure to form a key site called the peptidyltransferase centre (PTC), which is where the ribosome joins together amino acids when making new proteins for the cell. Questions remained about how these final assembly steps occur, and how Nmd3 is removed from the ribosome. Kargas et al. have now examined how the PTC forms by using a method known as cryo-electron microscopy to determine the structures that the ribosome forms at different stages of assembly. This revealed that when the last two ribosomal proteins integrate into the ribosome, the ribosomal RNA goes through large shape changes that evict Nmd3 from the PTC. Quality control factors then check the structure of the newly formed ribosome and, if it passes their checks that it works correctly, license it to start making cell proteins. This stage of ribosome assembly is likely to occur in the same way in all plant, animal and other eukaryotic species. The results presented by Kargas et al. will also help researchers to better understand the consequences of the mutations that affect ribosomal proteins in cancer cells. Ultimately, this knowledge may help to uncover new ways to treat cancer and ribosomopathies.

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Gale Document Number: GALE|A596804030