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Ribosomes synthesize all proteins in cells. Studies conducted primarily in yeast have revealed much about how ribosomes are assembled, but a Ludwig-Maximilians-Universitaet (LMU) team in Munich now reports that assembling ribosomes in human cells requires factors that have no counterparts in more model organisms. simple.
In each cell, hundreds of thousands of complex molecular machines called ribosomes manufacture new proteins, extending each growing chain at a rate of a few amino acids per second. It is therefore not surprising that the construction of these vital protein factories is itself a highly complex operation, involving more than 200 assembly factors transiently. Mature ribosomes are made up of approximately 80 proteins and four ribosomal RNAs. But it’s still not entirely clear how these components are assembled in the correct order to produce a functional ribosome. Furthermore, most of our knowledge of the process comes from studies conducted on model organisms such as bacteria and yeasts and may not necessarily be applicable to the cells of higher organisms. Researchers led by Professor Roland Beckmann (Gene Center, LMU Munich) have now discovered new details of crucial steps in the maturation of ribosomes in human cells.
Active ribosomes are made up of two separately assembled particles, which differ in size and interact with each other only after the first steps in protein synthesis have occurred on the smaller of the two (in human cells, the “40S subunit”). Beckmann’s team used cryo-electron microscopy to determine the structures of several precursors of the 40S subunit isolated from human cells and follow the course of its maturation. “This study follows on from an earlier project where we gained initial insights into the process,” says Michael Ameismeier. He is a PhD student on Beckmann’s team and lead author of the new report, which deals with the final stages of assembling the small subunit.
At this late stage of the process, one end of the ribosomal RNA associated with the small particle protrudes from the body of the immature subunit. The last step in the maturation of the 18S subunit is the removal of this now superfluous segment. To ensure that this reaction does not occur prematurely, the responsible enzyme – NOB1 – is kept in an inactive state until required. The new study shows that NOB1 activation is preceded by a conformational change that results in the detachment of a binding partner from the enzyme. This in turn triggers a structural rearrangement in NOB1 itself, which allows the enzyme to cut the protruding rRNA segment. “The activation of NOB1 is coordinated by another enzyme,” explains Ameismeier. Together with a protein we discovered – which is not found in yeast – this latter enzyme inserts itself like a wedge into the maturing 40S subunit, facilitating the decisive conformational change in NOB1. “
The authors also showed that yet another protein not found in yeast plays an (yet) enigmatic role in the maturation of the 40S subunit. “This demonstrates the importance of considering the human system separately from other experimental models,” says Beckmann. Using the evolutionarily simpler yeast system is sufficient for a basic understanding of the process. But some pathological syndromes have been linked to errors in ribosomal biogenesis in humans, which provides an obvious rationale for studying ribosomal assembly in human cell systems.
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