Helix to Beta Sheet Transitions Drive EAA1 Self Assembly & Potential Implications for Neurodegeneration

The Glutamate Transporter EAA1 is essential for regulating excitatory neurotransmitter levels in the central nervous system. We investigated how alternative splicing influences the structural stability and biophysical behavior of EAA1 peptides. Our work focuses on the molecular triggers that cause these specific splice variants to aggregate.

We characterized a significant conformational shift where the peptides transition from a native alpha helical state into beta sheet formations. This transition acts as the mechanical driver for the self assembly of the peptides into larger complexes. By mapping these dynamics, we demonstrated how splicing variations fundamentally alter the protein architecture and promote aggregation.

These findings suggest important potential implications for understanding protein misfolding and its possible role in neurological pathologies. Deciphering the pathways of helix to beta sheet transitions provides a structural framework that could lead to new therapeutic strategies for stabilizing transporter proteins.

Karagöl, A., & Karagöl, T. (2025). Helix-to-Beta-Sheet Transition Drives Self-Assembly of Glutamate Transporter EAA1 Splice Peptides. bioRxiv, 2025-08. https://doi.org/10.1101/2025.08.13.670123

Karagöl, A., & Karagöl, T. (2025). A Conserved Motif as an Evolutionary Kernel for β-Sheet Oligomerization Revealed by Divergence Analysis of Helix-to-Sheet Transitions in EAA1 Isoforms. bioRxiv, 2025-10. https://doi.org/10.1101/2025.10.02.679742