Dear All,

On Thursday 13.03 in the CN lecture hall we will host dr hab. Przemysław Grudnik, Malopolska Centre of Biotechnology, Jagiellonian University. His lecture will be entitled: Halfway to hypusine: Molecular basis of (deoxy)hypusination”. The lecture will take place at 3 p.m. in the CN lecture hall and it will be followed by a get together.

Abstract:

Hypusination, a critical post-translational modification of eukaryotic translation factor 5A (eIF5A), plays a key role in resolving ribosome stalling at polyproline stretches. Deoxyhypusine synthase (DHS) catalyzes the first step of this modification, converting eIF5A into its deoxyhypusine form. Despite its importance, the molecular mechanism of DHS remains incompletely understood. The recent identification of patient-derived DHS and eIF5A variants linked to neurodevelopmental disorders further underscores the significance of this process.

In our research, we elucidated the structure of the eIF5A-DHS complex using cryo-EM and captured DHS in the transition state of its catalytic reaction. Disease-associated DHS variants were found to disrupt complex formation and impair hypusination efficiency, providing new insights into the molecular basis of these disorders.

Beyond its enzymatic function, DHS appears to have a regulatory role through its interaction with ERK1/2 kinases. Our cryo-EM studies reveal that ERK2 sterically hinders substrate access to the DHS active site, inhibiting deoxyhypusination in vitro. Alanine scanning identified key residues mediating this interaction. Notably, activation of the Raf/MEK/ERK pathway weakens DHS-ERK1/2 binding while strengthening DHS-eIF5A association. Moreover, ERK1/2 kinase activity modulates the expression of DHS and eIF5A, highlighting a dual kinase-dependent and kinase-independent regulatory mechanism for hypusination.

In addition to structural and regulatory insights, we are also exploring DHS as a potential drug target. Crystallographic fragment screening has enabled the identification of promising ligands, facilitating the rational design of specific DHS inhibitors. These efforts provide valuable tools for studying hypusination and its broader impact on cellular processes and disease, with potential implications for novel therapeutic strategies.

Tomasz Wypych