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New Mechanism of Protein Synthesis Linked to Alzheimer’s

Anyone who has taken a biology or biochemistry class is familiar with the central dogma of the biological sciences, which describes the flow of genetic information. It dates back to Francis Crick in 1956 and can be simplified to the following concept: DNA encodes for RNA, and RNA encodes for proteins.

alzheimers word cloud with other words like healthA new study1 from the University of Utah reveals that this linear flow of information might not be as straightforward as we once thought.
The study takes a close look at the quality control process involved in protein synthesis. Protein-making machines known as ribosomes are responsible for stitching together the amino acid building blocks of proteins by using the sequence of messenger RNA (mRNA) as a blueprint.

When an error occurs, the ribosome will stall. This recruits an assembly of proteins charged with disassembling the ribosome, removing the faulty RNA and degrading the improperly made protein.
One particular quality control protein, known as Rqc2p, was found to play a surprising role. This protein — which is conserved across numerous species, from yeast to humans — binds to the stalled ribosome and promotes the continuation of protein synthesis without the use of the template mRNA sequence. Rqc2p accomplishes this unique function by binding to transfer RNA (tRNA) molecules carrying alanine or threonine amino acids.

The binding of specific tRNAs to the ribosome is generally facilitated by the sequence of the mRNA, but this protein manages to bypass what was once perceived as a crucial step in the protein-making process. This results in a nonsensical tag of alanines and threonines added to the end of improperly made proteins.
One potential purpose of this tag may be to target the dysfunctional protein for degradation. Accumulation of degenerate proteins has been linked to neurodegenerative diseases, such as Alzheimer’s and Huntington’s. The study authors suggest this new method of protein synthesis could contribute to disease prevention.

Peter Shen, Ph.D., and co-authors first arrived at this interesting finding when they used cryo-electron microscopy to determine the structure of the quality control proteins bound to a stalled ribosome. They observed that Rqc2p was bound to both the ribosome and a tRNA, which it had positioned adjacent to the improperly made protein chain. Seeing is not always believing, though, so the scientists involved in the study carried out numerous biochemical assays to validate this new method of protein synthesis.

The next steps will be to determine when this process takes place in the grand scheme of the cell cycle and what occurs when this process fails. While those key points are still unclear, what we know for sure is that our notion of how nature works is far more complicated than once perceived, and that old dogmas are subject to change with time and innovation.
The study was published in the Jan. 2, 2015, edition of Science


1. Rcq2p and 60S ribosomal subunits mediate mRNA-indpendent elongation of nascent chains. Peter S. Shen, Joseph Park, Yidan Qin, Xueming Li, Krishna Parsawar, Matthew H. Larson, James Cox, Yifan Cheng, Alan M. Lambowitz, Jonathan S. Weissman, Onn Brandman, Adam Frost. Science. Jan. 2, 2015: Vol. 347 no. 6217 pp. 75-78.