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Review
. 2014 Mar;15(3):245-54.
doi: 10.1111/tra.12140. Epub 2013 Dec 16.

The Sybtraps: control of synaptobrevin traffic by synaptophysin, α-synuclein and AP-180

Sarah L Gordon  1 , Michael A Cousin
Affiliations
Free PMC article
Review

The Sybtraps: control of synaptobrevin traffic by synaptophysin, α-synuclein and AP-180

Sarah L Gordon et al. Traffic. 2014 Mar.
Free PMC article

Abstract

Synaptobrevin II (sybII) is a key fusogenic molecule on synaptic vesicles (SVs) therefore the active maintenance of both its conformation and location in sufficient numbers on this organelle is critical in both mediating and sustaining neurotransmitter release. Recently three proteins have been identified having key roles in the presentation, trafficking and retrieval of sybII during the fusion and endocytosis of SVs. The nerve terminal protein α-synuclein catalyses sybII entry into SNARE complexes, whereas the monomeric adaptor protein AP-180 is required for sybII retrieval during SV endocytosis. Overarching these events is the tetraspan SV protein synaptophysin, which is a major sybII interaction partner on the SV. This review will evaluate recent studies to propose working models for the control of sybII traffic by synaptophysin and other Sybtraps (sybII trafficking partners) and suggest how dysfunction in sybII traffic may contribute to human disease.

Keywords: AP-180; endocytosis; presynapse; synaptobrevin; synaptophysin; vesicle; α-synuclein.

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Figures

Figure 1
Figure 1. The Sybtraps: sybII trafficking partners
Three unrelated proteins interact at separate sites on sybII to control its trafficking and conformation. The integral SV protein synaptophysin is postulated to share a transmembrane (TM) domain interaction with sybII, leaving its cytoplasmic C-terminus (with numerous tyrosine repeats) free to associate with other endocytic molecules. The SV-associated protein α-synuclein interacts with the extreme N-terminus of sybII via its acidic C-terminus. It also binds lipid membranes via its membrane associated region (MAR) on its N-terminus inducing formation of an α-helix, whereas its non-amyloid component (NAC) domain mediates its aggregation. The monomeric endocytic adaptors AP180 and CALM interact with the sybII SNARE motif via their ANTH domains. They can also recruit both clathrin and the AP-2 adaptor complex via multiple interaction motifs on the remaining protein. Numbers indicate amino acid primary sequence.
Figure 2
Figure 2. Sybtrap control of sybII during SV recycling
A) SybII (blue) is complexed with synaptophysin (red) on the synaptic vesicle in resting nerve terminals via their transmembrane domains. At some point before entry of sybII into the SNARE complex, α-synuclein (purple) interacts with the N-terminus of sybII via its acidic C-terminus. α-Synuclein facilitates the assembly of SNARE complexes between sybII and plasma membrane syntaxin (green)/SNAP-25 (yellow) dimers. Entry of sybII into the trans-SNARE complex displaces synaptophysin from sybII. α-Synuclein remains associated with the assembled SNARE complex until synaptic vesicle fusion is triggered. B) After synaptic vesicle fusion, the cis-SNARE complex is broken apart by the combined action of N-ethylmaleimide-sensitive factor (NSF) and soluble NSF-attachment proteins (SNAPs). Free monomeric sybII in the plasma membrane is prevented from re-entering futile cis-SNARE complexes via a shared transmembrane domain interaction with synaptophysin. This association retains sybII in a ‘retrieval competent’ conformation, where its SNARE motif is accessible to the ANTH domain of the monomeric adaptor AP180 (orange). The avidity of this retrieval complex may be increased further via recruitment of AP-2 (pink) by the tyrosine motifs on the C-terminus of synaptophysin and further still by the subsequent interaction between AP180 and AP-2.
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