How "protein factories" mature

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Ribosomes are small "factories" in which proteins are assembled according to genetic construction plans. The maturation of ribosomes, of which every human cell contains up to a million, is a complicated, multi-phase process. Now, with the aid of cryo-electron microscopy, scientists from Heidelberg University and Ludwig-Maximilians-Universität München have been able to clarify an important step in ribosomal formation. These "protein factories" consist of two ribosomal subunits and the scientists have shown that the smaller one "peels out" of a precursor complex and does not break off en bloc, as was so far assumed. The findings were published in the journal "Science".

A ribosome is a giant molecule - a complex structure consisting of special proteins and ribonucleic acid (RNA). Yet how the assembly of ribosomes exactly happens is not yet entirely understood. In past years Heidelberg scientists have succeeded in reconstructing elementary steps of ribosome formation in a test-tube. Ribosomes are composed of two subunits of different sizes, each of which is formed from precursor complexes, the so-called pre-ribosomes. These pre-ribosomes also contain the ribosomal RNA chains, which are initially linked to one another in a precursor piece. "There was unclarity to date on how and when these RNA chains are separated from one another to finally form the mature subunits," says Ed Hurt from Heidelberg University Biochemistry Center (BZH).

In cooperation with structural biologists from Munich, the Heidelberg scientists have now been able to image important assembly steps - both biochemically and by means of high-resolution cryo-electron microscopy. That also includes the multi-step process with which the small 40S subunits are "peeled out" of a giant precursor complex, the 90S pre-ribosome. It was primarily through biochemical analyses that Ed Hurt’s team found the first indications of this mechanism, which contradicted previous ideas about an en bloc separation.

Separating the RNA chain in the 90S pre-ribosome into two sections requires special "cellular assembly operators", so-called biogenesis factors. They prepare the ribosome RNA for the cleavage at the planned locations so that RNA scissors, the enzyme Utp24, can make the cut at two specific sites and at a coordinated time. At first, the 40S subunit is encapsulated in a protein shell. In a sequence of additional reactions this ’exoskeleton’ separates off from the immature version of the subunit and releases it. "The 40S subunit runs through a kind of moulting with individual pre-modules detaching themselves layer by layer," Prof. Hurt explains. Step by step the Munich experts on cryo-electron microscopy were able to calculate the complex three-dimensional molecular structures formed during the successive shedding process from their images.

With their results the researchers hope to contribute to a better understanding of ribosomopathies. These are illnesses caused by faults in ribosome formation. The research projects were conducted in the course of the ERC Advanced Grant with which the European Research Council is funding Prof. Hurt’s investigations.

J. Cheng, B. Lau, G. La Venuta, M. Ameismeier, O. Berninghausen, E. Hurt, R. Beckmann (2020): 90S pre-ribosome transformation into the primordial 40S subunit. In: Science 369, 1470-1476.

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