2024-01-24 18:32:43
Once again, teamwork and once again a discovery to fight the disease is recognized by the BBVA Foundation Frontiers of Knowledge Awards in its Biology and Biomedicine category. In this case, the first step was taken by professors Ulrich Hartl, from the Max Planck Institute of Biochemistry, in Germany, and researcher Arthur Horwich, from Yale University, in the USA. Both revealed the cellular machinery on which protein folding depends, an essential process for them to carry out their functions in the body. Later, scientist Kazutoshi Mori, from Kyoto University, in Japan, and researcher Peter Walter, from the University of California, in the USA, identified the response mechanism that is triggered to refold or eliminate proteins when they do not fold properly.
The chaperones
All the instructions we need to develop, survive and reproduce reside in the DNA of our cells. But the main ones responsible for carrying out these functions are proteins and “to fulfill their function” – as explained in the jury report – “they must adopt certain three-dimensional structures that are achieved in cells with the help of a group of proteins called chaperones. ”. The four winners made two key discoveries in this field: Hartl and Horwich discovered the first cellular pathway that regulates protein folding, thanks to the discovery of the role played by the so-called chaperone Hsp60, while Mori and Walter identified the mechanism used by cells when protein folding fails, acting on them, either to try to fold them correctly or, if this is not possible, destroy them.
medicinal applications
These findings about a biological process so fundamental for life have enormous biomedical implications, since the molecular machinery that controls both protein folding and the response to failures in this mechanism is involved in the origin of multiple diseases, from cancer to neurodegenerative disorders such as Alzheimer’s, Parkinson’s and amyotrophic lateral sclerosis (ALS), or the aging process itself. For all this, the jury concludes its minutes by highlighting that the “revolutionary findings” of the four winners have revealed “how cells control the biogenesis and degradation of proteins, something fundamental not only for physiology, but also for understanding the origin and design therapies for many diseases.”
“The two discoveries recognized by the award are fundamental for the health of each cell and therefore of our body. In particular, there are some diseases that are due to the accumulation of proteins that have not folded well and that therefore become toxic,” explains Óscar Marín, professor of Neuroscience and director of the Center for Neurodevelopmental Disorders of the MRC in King’s College London, in the United Kingdom, who acted as secretary of the jury. “If proteins do not fold properly, this causes loss of cell function, for example, in some degenerative diseases of the nervous system.”
“The findings of the four winners are important not only for our understanding of fundamental biology, but also because they lead to a new way of understanding diseases and treating them better in the future,” highlights Dario Alessi, director of the Unit. of Protein Phosphorylation and Ubiquitination at the MRC at the University of Dundee (United Kingdom) and member of the jury. “Currently there is enormous interest, especially in the field of neurodegeneration, to
to drive therapeutic pathways that can keep proteins folded correctly in cells, and also to drive the process of removing unfolded proteins, because this is harmful to cells. Furthermore, in the case of cancer, it is thought that if the enzymes that cause protein folding in some types of tumors could be inhibited, this could increase the ability to eliminate cancer cells that grow very quickly and are highly dependent on this process. ”.
Dismantling a Nobel Prize
In 1972, Christian Anfinsen received the Nobel Prize for a series of experiments that demonstrated that certain small proteins fold spontaneously inside a test tube. His work established the idea, which Hartl and Horwich would eventually disprove, that all proteins, even within cells, fold spontaneously. In the 1980s, Hartl and Horwich, separately, studied how proteins enter compartments called mitochondria that exist inside cells and are surrounded by a membrane. Hartl had verified that, to cross that membrane, the proteins had to be unfolded, and this result led Horwich to explore an unusual hypothesis: “Perhaps proteins, at least within cells, do not fold spontaneously after crossing the mitochondrial membrane,” he recalls.
In his laboratory, the researcher had mutant versions of yeast. When examining them with his team to check how the proteins entered the mitochondria, he thought he found that, in one of them, the proteins crossed the membrane correctly, but, once inside, they were unable to activate their functions. If the result was confirmed, he would mean that the proteins within these cells did not fold spontaneously: there had to be something that prevented it. “We were very scared by the result because we believed that no one in the world would believe it. It was a heresy against the principles of Anfinsen,” says Horwich.
Coincidentally, a couple of months later, Horwich received a phone call from Hartl’s laboratory. Without yet knowing the result of that “heretical” experiment, Hartl had also questioned the hypothesis of spontaneous protein folding within cells and was interested in examining this process in Horwich mutant yeasts. For Horwich, this call was providential, giving him access to the sophisticated experimental techniques of Hartl’s laboratory that would allow him to reconstruct the process of protein entry into the mitochondria in complete detail.
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