Recently we have discussed (Milovanovic and De Camilli, (2017) Neuron) how several features of SV clusters suggest that they may be part of a distinct liquid phase in the cytosol. For example, SV clusters have sharp boundaries, exclude other organelles, vesicles in these clusters are mobile, and SVs can be exchanged with vesicles outside the cluster. Thus, SV clusters may represent a distinct liquid phase in which one component of the phase is synaptic vesicles and the other component is proteins of the intervening matrix. Several proteins associated with synaptic vesicles have been identified, the major one being synapsin 1. Synapsin 1 is a highly abundant protein at the nerve terminals, it binds SVs and contains an extended low complexity region. The last property is a characteristic of several proteins that self-separate into a liquid phase.
Figure: 3D model of nerve terminal from FIB-SEM images. Synaptic vesicles (blue) form a tight cluster; endoplasmic reticulum (yellow), mitochondria (green), and endosomal structures (light blue) are also shown. Figure prepared by Dr. Yumei Wu, Yale School of Medicine.
In our latest study, we show that synapsin 1 forms a distinct liquid phase in an aqueous environment. Synapsin 1 exchanges readily between the phase where it is enriched and the surrounding medium. Additional synapsin 1 binding scaffolding proteins further modulate this phase but are not necessary for its formation. Importantly, synapsin 1 can capture small lipid vesicles into its phase. The phase of synapsin 1 rapidly disassembles upon phosphorylation by CaMKII, mimicking the dispersion of synapsin 1 that occurs at presynaptic boutons upon simulation. Thus, a minimal system of synapsin (with or without its binding partners) may sequester lipid vesicles, forming a distinct liquid phase. Given the high degree of specificity of clusters for SVs, there must be additional factors that help provide specificity. Nonetheless, our results support the hypothesis that phase separation plays an important role in the clustering of SVs at synapses. Furthermore, clusters of other organelles in cells (e.g., a cloud of vesicles at the ER exit sites, vesicles at the Golgi complex, or nascent clusters of viral particles) might represent similar examples of a liquid phase.
References
[1] Synaptic vesicle clusters at synapses: a distinct liquid phase? Milovanovic D and De Camilli P. (2017) Neuron, 93: 995
[2] A liquid phase of synapsin and lipid vesicles. Science. Milovanovic D, Wu Y, Bian X, De Camilli P. (2018) DOI: 10.1126/science.aat5671
PubMed link [1]
Link to article [1]
PubMed link [2]
Link to article [2]