Ribosomes, which use a fixed genetic programme to manufacture cell proteins, also form according to a strict hierarchical plan. In an interdisciplinary approach, the research teams of Prof. Dr. Ed Hurt of the Heidelberg University Biochemistry Center (BZH) and Prof. Dr. André Hoelz of the California Institute of Technology (Caltech) in Pasadena (USA) have decoded the mechanism that regulates this process. They discovered a previously unknown protein that regulates the processes in the cell nucleus that permit the cell to incorporate ribosomal proteins into the developing pre-ribosome in the correct order. The results of their research were published online in "Molecular Cell."
Ribosomes are complexly structured cellular nanomachines consisting of four ribonucleic acids and approximately 80 different ribosomal proteins (r-proteins). They are responsible for synthesising protein chains. "Correct ribosomal formation is of elementary importance in cell division and propagation. Their structure is highly complicated because all ribosomal proteins are added to the developing pre-ribosome in a strict sequence, with approximately 200 helper proteins assisting in the process," says Ed Hurt.
In eukaryotes, new ribosomes are formed primarily in the cell nucleus. The r-proteins needed for their formation must travel from the cell plasma to the site in the nucleus where the ribosomes are manufactured, called the nucleolus. Until now, scientists knew only that r-proteins were built into the newly forming ribosome following a strict hierarchy -- r-protein B comes after r-protein A and so on. "But the question of how the strict sequence is ensured and who is responsible remained largely unanswered," explains Prof. Hurt.
The researchers have now been able to demonstrate that the newly discovered protein, called the assembly chaperone of L4 or Acl4, regulates the orderly integration of ribosomal protein L4 into the early pre-ribosome. "This employs a well-known everyday concept, like an usher holding a seat open until the correct occupant arrives," explains the researcher.
Using new investigative procedures, the two primary authors of the publication, Dr. Philipp Stelter of the BZH and Ferdinand Huber of Caltech, were able to decode the detection mechanism between the L4 r-protein and the developing ribosome. According to the researchers, the underlying basis is a eukaryote-specific extension of the L4 ribosomal protein that comes into contact with the surface of the ribosome and is released for assembly by the Acl4 helper protein. If these interactions are hindered by insufficient production of the r-protein or an error in the growing ribosome, the helper protein remains bound and prevents the development of a faulty ribosome.
The collaboration between the researchers of the Heidelberg University Biochemistry Center and the California Institute of Technology offered an opportunity to combine traditional and newly developed methods in cellular biology, biochemistry and biophysics. "This was pivotal for the detailed characterisation of the newly discovered mechanisms and the participating components," emphasises Ed Hurt.
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