Synaptic Vesicle Clusters at Synapses: A Distinct Liquid Phase?

Milovanović, Dragomir; Camilli, Pietro De

doi:10.1016/j.neuron.2017.02.013

Cited by 102 publications

(99 citation statements)

References 95 publications

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“…The ability of TFG to tether inner COPII-coated carriers is highly reminiscent of the functions proposed for synapsin and synuclein in synaptic vesicle clustering (72)(73)(74)(75)(76). All three proteins self-associate and harbor disordered regions composed largely of proline, glutamine, glycine, and serine, which form relatively weak but multivalent interactions with vesicle-associated proteins (77)(78)(79).…”

Section: Discussionmentioning

confidence: 95%

TFG facilitates outer coat disassembly on COPII transport carriers to promote tethering and fusion with ER–Golgi intermediate compartments

Hanna

Block

Frankel

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The conserved coat protein complex II (COPII) mediates the initial steps of secretory protein trafficking by assembling onto subdomains of the endoplasmic reticulum (ER) in two layers to generate cargo-laden transport carriers that ultimately fuse with an adjacent ER–Golgi intermediate compartment (ERGIC). Here, we demonstrate that Trk-fused gene (TFG) binds directly to the inner layer of the COPII coat. Specifically, the TFG C terminus interacts with Sec23 through a shared interface with the outer COPII coat and the cargo receptor Tango1/cTAGE5. Our findings indicate that TFG binding to Sec23 outcompetes these other associations in a concentration-dependent manner and ultimately promotes outer coat dissociation. Additionally, we demonstrate that TFG tethers vesicles harboring the inner COPII coat, which contributes to their clustering between the ER and ERGIC in cells. Together, our studies define a mechanism by which COPII transport carriers are retained locally at the ER/ERGIC interface after outer coat disassembly, which is a prerequisite for fusion with ERGIC membranes.

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Section: Discussionmentioning

confidence: 95%

TFG facilitates outer coat disassembly on COPII transport carriers to promote tethering and fusion with ER–Golgi intermediate compartments

Hanna

Block

Frankel

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…SVs are tightly packed in these structures, which are well-distinct from the surrounding cytoplasm, although there is no evidence for a restraining boundary (1). Vesicles intermix within the clusters (2) and can be exchanged between them (3).…”

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confidence: 99%

“…S1). This prompted us to hypothesize (1) that synapsin may be a key constituent of a biomolecular condensate that includes SVs.…”

mentioning

confidence: 99%

A liquid phase of synapsin and lipid vesicles

Milovanović

Bian

et al. 2018

Science

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407

419

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Neurotransmitter containing synaptic vesicles (SVs) form tight clusters at synapses. These clusters act as a reservoir from which SVs are drawn for exocytosis during sustained activity. Several components associated with synaptic vesicles likely to help forming such clusters have been reported, including synapsin. Here we found that synapsin can form a distinct liquid phase in an aqueous environment. Other scaffolding proteins could co-assemble into this condensate, but were not necessary for its formation. Importantly, the synapsin phase could capture small lipid vesicles. The synapsin phase rapidly disassembled upon phosphorylation by calcium/calmodulin-dependent protein kinase II (CaMKII), mimicking the dispersion of synapsin 1 that occurs at presynaptic sites upon stimulation. Thus, principles of liquid-liquid phase separation may apply to the clustering of SVs at synapses.

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“…Upon release of the inner COPII coat, affinity for the phase separated ER/ERGIC interface is diminished, enabling fusion of the naked transport carriers with tightly juxtaposed ERGIC membranes. In this model, the capture and release of COPII transport carriers parallels synaptic vesicle clustering mediated by synapsin phase separation at pre‐synaptic terminals …”

Section: Introductionmentioning

confidence: 99%

Membrane Transport at an Organelle Interface in the Early Secretory Pathway: Take Your Coat Off and Stay a While

et al. 2018

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Most metazoan organisms have evolved a mildly acidified and calcium diminished sorting hub in the early secretory pathway commonly referred to as the Endoplasmic Reticulum-Golgi intermediate compartment (ERGIC). These membranous vesicular-tubular clusters are found tightly juxtaposed to ER subdomains that are competent for the production of COPII-coated transport carriers. In contrast to many unicellular systems, metazoan COPII carriers largely transit just a few hundred nanometers to the ERGIC, prior to COPI-dependent transport on to the cis-Golgi. The mechanisms underlying formation and maintenance of ERGIC membranes are poorly defined. However, recent evidence suggests an important role for Trk-fused gene (TFG) in regulating the integrity of the ER/ERGIC interface. Moreover, in the absence of cytoskeletal elements to scaffold tracks on which COPII carriers might move, TFG appears to promote anterograde cargo transport by locally tethering COPII carriers adjacent to ERGIC membranes. This action, regulated in part by the intrinsically disordered domain of TFG, provides sufficient time for COPII coat disassembly prior to heterotypic membrane fusion and cargo delivery to the ERGIC.

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Synaptic Vesicle Clusters at Synapses: A Distinct Liquid Phase?

Cited by 102 publications

References 95 publications

TFG facilitates outer coat disassembly on COPII transport carriers to promote tethering and fusion with ER–Golgi intermediate compartments

TFG facilitates outer coat disassembly on COPII transport carriers to promote tethering and fusion with ER–Golgi intermediate compartments

A liquid phase of synapsin and lipid vesicles

Membrane Transport at an Organelle Interface in the Early Secretory Pathway: Take Your Coat Off and Stay a While

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