12.04.2023 change 12.04.2023

Team from Jagiellonian University describes important cellular mechanism

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Scientists from the Jagiellonian University described in Nature Communications a key discovery concerning an extremely important modification of proteins produced in cells. The mechanism called hypusination is important in the development of cancer, neurodegenerative diseases and diabetes.

Once the cell produces a protein based on genetic information, it processes it in various ways. This is called posttranslational modification.

Researchers from the Małopolska Centre of Biotechnology of the Jagiellonian University explain that hypusination, discovered in the 1980s, is the most unique modification of this type described so far for only one protein - eIF5A.

The modified protein is critical for numerous cellular processes, including cell growth and division. For this reason, hypusination disorders may be related to the formation of some cancers, neurodegenerative diseases or diabetes.

The modification is that only one amino acid in this protein is converted from lysine into hypusine.

The hypusination process is carried out by two enzymes – deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH), but its mechanism has so far remained a mystery.

Elżbieta Wątor, a doctoral candidate at the Małopolska Centre of Biotechnology and the first author of the paper, said: “Hypusination is a little-known, but essential process for every living cell. During my university curriculum, I never heard about this unique process, and only my supervisor Dr. Przemysław Grudnik introduced this term to my dictionary. I am really happy that we were able to broaden our understanding of the molecular mechanism of hypusination. By revealing the detailed structure of the eIF5A-DHS complex, we have gained new insights into how DHS recognises and modifies eIF5A.”

The discovery was made by using a whole range of the latest research methods.

Dr. Piotr Wilk, the second author of the paper, said: “Application of X-ray crystallography allowed us to visualize and analyse fine structural rearrangements taking place along the catalytic cycle of DHS. However, we were not able to visualize the interaction between eIF5A-DHS. Fortunately, CryoEM, allowed us to complete the picture by determining the complex of DHS with its substrate protein bound. Our study is a great example of the potential of structural biology in explaining long-standing biological questions.”

The researchers used the Titan Krios G3i high-end cryo-electron microscope located at the SOLARIS National Synchrotron Radiation Centre and the BESSY II synchrotron in Belin.

Due to the importance of hypusination to cells, the discovery could have significant practical benefits over time.

Co-author Dr. Przemysław Grudnik said: “The understanding of eIF5A-DHS interaction could have implications for the development of new treatments for diseases related to aberrant protein translation, such as cancer and neurodegenerative disorders. We aim to further exploit our structural understanding of the deoxyhypusination complex to develop new chemicals targeting it.”

The research was financed as part of the NCN OPUS 17 and NCN PRELUDIUM 18 projects.

Find out more in the source article. (PAP)

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