pH-Dependent Membrane Binding Specificity of Synaptogyrins 1-3 Provides Mechanistic Insights into Synaptic Vesicle Regulation and Neurological Disease

Synaptogyrins (SYNGRs) are integral synaptic vesicle proteins that contribute to neurotransmitter release and synaptic plasticity. Alterations in vesicular pH, as observed in ageing and Alzheimer’s disease, may influence synaptogyrin function, yet the molecular mechanisms remain poorly understood. We compared synaptogyrin-1 (SYNGR1, pI 4.5) and synaptogyrin-3 (SYNGR3, pI 8.4), two structurally similar isoforms with distinct electrostatic properties. Using 50ns all-atom molecular dynamics simulations in realistic lipid bilayers at resting (pH 5.5) and active (pH 7.25) conditions, we examined how vesicular pH modulates protein conformation, membrane binding, and stability. Despite near-identical backbones (RMSD 1.27 Å), SYNGR1 and SYNGR3 displayed divergent pH-dependent dynamics. Comparative analysis revealed that SYNGR1’s resting state closely resembled the active state of SYNGR3, suggesting functional convergence during vesicle recycling. Multivariate amino acid profilling was conducted using homologous residue profiles. Consistent with epistatic potential, ClinVar-reported damaging variants in SYNGR1 clustered within regions of low structural mimicry, whereas SYNGR3 variants localized to conserved regions. These findings identify pH-dependent electrostatic modulation as a determinant of synaptogyrin behaviour and provide a framework for understanding their roles in synaptic vesicle cycling. The distinct conformational and mutational landscapes of SYNGR1 and SYNGR3 highlight potential mechanisms by which pH dysregulation in neurodegeneration may impair synaptic function.