Retinal photoreceptors transmit light signals to their postsynaptic neurons with high precision, speed and without fatigue. This high-throughput neurotransmission relies on a sophisticated molecular machinery centered on a presynaptic organelle, the synaptic ribbon (SR). A hallmark of SRs is the recruitment of synaptic vesicles (SVs) from the cytoplasmic SV pool via “tethering”. However, the identity of the tether and the mechanism underlying SV tethering were unknown.
A new study published in the Journal of Cell Biology now identifies the scaffold protein Piccolino as the molecular bridge connecting synaptic vesicles to the ribbon. In photoreceptors lacking Piccolino, the structural integrity of the ribbon is impaired and vesicle tethering is almost completely abolished.
We are very happy to have contributed to this exciting project led by Kaspar Gierke and Johann Helmut Brandstätter from FAU Erlangen-Nürnberg’s Animal Physiology/Neurobiology group, in collaboration with Carolin Wichmann and colleagues at the University of Göttingen.
Nancy Mejia Villagran and Sonja Kirsch of the Computational Biology team used multiscale molecular dynamics simulations to investigate an amphipathic lipid-packing sensor motif in the N-terminus of Piccolino (see snapshot below). The simulations showed that this motif preferentially binds to the highly curved and loosely packed membranes characteristic of synaptic vesicles. Upon binding, it inserts into the membrane and can further promote membrane curvature.
Together with electron tomography, high-resolution nanoscopy, and biochemical experiments, these results support a model in which the N-terminus of Piccolino anchors to the vesicle membrane, while its C-terminus remains associated with the synaptic ribbon. Piccolino thereby acts as a molecular tether that captures and retains synaptic vesicles at the ribbon.
A great example of how experiments and simulations can work together to resolve the molecular machinery underlying neuronal communication.
Article: Gierke et al. J Cell Biol (2026) 225 (9): e202509110 https://doi.org/10.1083/jcb.202509110
Video description: All-atom molecular dynamics simulation of the Piccolo ALPS motif attaching to a synaptic vesicle (SV)-like membrane. The upper leaflet lipids are shown in green, the lower leaflet lipids in pink and cholesterol is shown in orange. The protein backbone is colored in black and the side chains are colored by property: strongly hydrophobic: yellow, weakly hydrophobic: black, polar uncharged: magenta, basic: blue. The protein inserts into the membrane and orients itself so that hydrophobic residues face the bilayer core, while polar and basic residues face the headgroups and solvent.
Top image description: Cross-section through a bicelle whose central region has a lipid composition resembling that of synaptic vesicles. The ALPS motif of the protein Piccolino is bound to this region, inducing curvature of the bicelle. Rim lipids are shown in blue and yellow, synaptic-vesicle membrane lipids in orange, and the protein in green.