A research team from the Malopolska Centre of Biotechnology at Jagiellonian University (MCB UJ), led by dr hab. Przemysław Grudnik, in collaboration with scientists from the Medical College of Wisconsin, has uncovered an unusual role of the ERK1/2 kinases in the regulation of a unique post translational modification, hypusination. This breakthrough not only bridges a gap in our understanding of the mechanisms controlling hypusination, an essential process for the human body, but also reveals a surprising function of ERK1/2. These findings have recently been published in the scientific journal “Cell Reports”.
Hypusination is a highly specific modification of eukaryotic translation factor 5A (eIF5A), and deoxyhypusine synthase (DHPS) is responsible for catalyzing the first and limiting step of this process. Hypusination enables eIF5A to facilitate the synthesis of other proteins in the cells, which is a fundamental process. Despite its critical function in cellular homeostasis, the regulation of hypusination remains elusive. Researchers at MCB have started to unravel the mechanisms controlling hypusination and have shown the new unexpected finding that the extracellular signal regulated kinases 1/2 (ERK1/2) perform a non kinase function by directly interacting with DHPS to regulate hypusination. ERK1/2 are key enzymes in a signaling pathway, which is crucial in regulating cell growth, differentiation, and cell survival in human bodies. Until now, these proteins have been studied for their enzymatic (kinase) activity, which allows them to activate other proteins through phosphorylation (adding phosphate groups).
Researchers at MCB employed cryo-electron microscopy (cryo EM) to study the structure of the DHPS ERK2 complex. The data revealed that ERK2 binds to DHPS at the entrance to its active site, effectively blocking access for eIF5A. The findings also highlight how cellular signaling via the Raf/MEK/ERK pathway modulates ERK1/2 association with DHPS. When this pathway is activated, the interaction between ERK1/2 and DHPS decreases, allowing eIF5A to be hypusinated. Moreover, ERK1/2’s kinase activity controls how much DHPS and eIF5A the cell produces. This discovery provides fresh insights into how cells regulate essential processes such as protein synthesis in response to external signals.
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Image: Dr hab. Przemysław Grudnik (on the right) and Paweł Kochanowski (on the left) are holding a model of the DHPS-ERK2 complex.