pH Shifts Altering Synaptogyrins During Synaptic Vesicle Regulation

Synaptogyrins are vital proteins that regulate neurotransmitter release and synaptic plasticity within synaptic vesicles. Changes in vesicular pH are frequently observed in ageing and neurodegenerative conditions like Alzheimer's disease, yet the molecular impact on synaptogyrin function has remained largely unexplored. In our latest preprint, my brother Alper Karagöl and I investigated these underlying mechanisms by comparing two closely related isoforms, synaptogyrin 1 and synaptogyrin 3.

For this study, we executed all atom molecular dynamics simulations to analyze how these proteins behave in realistic lipid bilayers under both resting conditions at pH 5.5 and active conditions at pH 7.25. Our analysis revealed that the resting state of synaptogyrin 1 closely mimicked the active state of synaptogyrin 3, indicating a functional convergence during vesicle recycling. Additionally, we conducted multivariate amino acid profiling and found that clinically reported damaging variants in synaptogyrin 1 cluster in regions with low structural mimicry, whereas mutations in synaptogyrin 3 appear in highly conserved regions.

These results emphasize that pH modulated electrostatic changes act as a primary determinant of synaptogyrin behavior. By mapping the distinct conformational and mutational landscapes of these two isoforms, we provide a concrete structural framework for understanding how pH dysregulation contributes to synaptic impairment in neurodegeneration. We hope these mechanistic insights will guide future therapeutic strategies targeting synaptic vesicle regulation.

Karagöl, T., & Karagöl, A. (2025). pH-Dependent Membrane Binding Specificity of Synaptogyrins 1-3 Provides Mechanistic Insights into Synaptic Vesicle Regulation and Neurological Disease. https://doi.org/10.1101/2025.03.03.641025