On March 31, Elena Spinetti successfully defended her doctoral dissertation, titled “Early events in the ectivation of membrane protein controlled signaling pathways.” As part of the research group led by FIAS Senior Fellow Roberto Covino, she studied a protein that plays a role in diseases such as diabetes.

Spinetti started her PhD in the Covino lab in 2021, following a three-month Erasmus+ postgraduate internship at FIAS. She investigated transmembrane proteins and disordered regions using molecular dynamics simulations. The focus was on transmembrane proteins that cross the membrane bilayer only once, while disordered proteins or regions are characterized by the absence of a defined secondary structure and high flexibility. Both kinds of protein domains are particularly difficult to resolve structurally. Structural modeling and molecular dynamics enable the research group to investigate their structure and dynamics. Spinetti used all-atom and coarse-grained simulations to study various aspects of these proteins.

her main project involved the study of human IRE1⍺, a sensor protein in the endoplasmic reticulum. The function of IRE1⍺ is to monitor the protein production in the ER and, if unfolded proteins accumulate, to act to save the cell from toxic effects or lead it to apoptosis. Its malfunction is involved in several diseases, including diabetes and neurological diseases. 

Spinetti’s work contributed to our understanding of IRE1α activation by elucidating its mode of binding to unfolded peptides and characterizing new binding hotspots. She also investigated how its disordered domains contribute to phase separationleading to the formation of oligomers.  Moreover, the doctoral student tailored deep learning models for the design of de novo binders to IRE1α that could contribute to our understanding of its binding partners.

She also dissected the importance of the conformations of the transmembrane region of the HIV envelope protein for antibody binding. Using coarse-grained simulations, she investigated the disordered regions of IGF1BP2, an mRNA-binding protein that is important for embryonic development and has been linked to tumorigenesis.

In the future, Spinetti hopes to work in the biotech and pharmaceutical industries.

Publications:

Kettel, P., Marosits, L., Spinetti, E., Rechberger, M., Giannini, C., Radler, P., Niedermoser, I., Fischer, I., Versteeg, G.A., Loose, M. and Covino, R., (2024). Disordered regions in the IRE1α ER lumenal domain mediate its stress-induced clustering. EMBO Journal, 43(20), pp.4668-4698. 

Hornegger, H., Anisimova, A.S., Muratovic, A., Bourgeois, B., Spinetti, E., Niedermoser, I., Covino, R., Madl, T. and Karagöz, G.E.,(2024). IGF2BP1 phosphorylation in the disordered linkers regulates ribonucleoprotein condensate formation and RNA metabolism. Nature Communications, 15(1), p.9054.

Spinetti, E., Karagöz, G. E., Covino R. (2025). The Structural Dynamics of IRE1 and its Interaction with Unfolded Peptides. eLife, 14:RP106716