Repository: Freie Universität Berlin, Math Department

Independently engaging protein tethers of different length enhance synaptic vesicle trafficking to the plasma membrane

Berns, Manon M. M. and Yildiz, Mirza and Winkelmann, Stefanie and Walter, Alexander M. (2025) Independently engaging protein tethers of different length enhance synaptic vesicle trafficking to the plasma membrane. The Journal of Physiology .

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Official URL: https://doi.org/10.1113/JP286651

Abstract

Synaptic vesicle (SV) trafficking toward the plasma membrane (PM) and subsequent SV maturation are essential for neurotransmitter release. These processes, including SV docking and priming, are co-ordinated by various proteins, such as SNAREs, Munc13 and synaptotagmin (Syt), which connect (tether) the SV to the PM. Here, we investigated how tethers of varying lengths mediate SV docking using a simplified mathematical model. The heights of the three tether types, as estimated from the structures of the SNARE complex, Munc13 and Syt, defined the SV–PM distance ranges for tether formation. Geometric considerations linked SV–PM distances to the probability and rate of tether formation. We assumed that SV tethering constrains SV motility and that multiple tethers are associated by independent interactions. The model predicted that forming multiple tethers favours shorter SV–PM distances. Although tethers acted independently in the model, their geometrical properties often caused their sequential assembly, from longer ones (Munc13/Syt), which accelerated SV movement towards the PM, to shorter ones (SNAREs), which stabilized PM-proximal SVs. Modifying tether lengths or numbers affected SV trafficking. The independent implementation of tethering proteins enabled their selective removal to mimic gene knockout (KO) situations. This showed that simulated SV–PM distance distributions qualitatively aligned with published electron microscopy studies upon removal of SNARE and Syt tethers, whereas Munc13 KO data were best approximated when assuming additional disruption of SNARE tethers. Thus, although salient features of SV docking can be accounted for by independent tethering alone, our results suggest that functional tether interactions not yet featured in our model are crucial for biological function.

Item Type:Article
Subjects:Mathematical and Computer Sciences
Mathematical and Computer Sciences > Mathematics
Mathematical and Computer Sciences > Mathematics > Applied Mathematics
Divisions:Department of Mathematics and Computer Science > Institute of Mathematics
ID Code:3272
Deposited By: Lukas-Maximilian Jaeger
Deposited On:16 May 2025 10:39
Last Modified:16 May 2025 10:39

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