Molecular Signatures Underlying Synaptic Vesicle Cargo Retrieval

Mori, Yasunori; Takamori, Shigeo

doi:10.3389/fncel.2017.00422

Cited by 13 publications

(21 citation statements)

References 124 publications

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“…Clathrin-mediated vesicle trafficking in eukaryotes is involved in most endocytic pathways ( 1 ), trafficking from trans-Golgi network ( 2 ), trafficking from endosomes ( 3 ), and also in the critical function of regenerating synaptic vesicles (SVs) ( 4 – 6 ). Clathrin and its associated adaptor/accessory proteins together carry out three important functions, which include engaging with cargo and membrane and also generating negative curvature on the membrane such that the cargo becomes encapsulated in a vesicle.…”

Section: Introductionmentioning

confidence: 99%

The structures of natively assembled clathrin-coated vesicles

et al. 2020

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Clathrin-coated vesicles mediate trafficking of proteins and nutrients in the cell and between organelles. Proteins included in the clathrin-coated vesicles (CCVs) category include clathrin heavy chain (CHC), clathrin light chain (CLC), and a variety of adaptor protein complexes. Much is known about the structures of the individual CCV components, but data are lacking about the structures of the fully assembled complexes together with membrane and in complex with cargo. Here, we determined the structures of natively assembled CCVs in a variety of geometries. We show that the adaptor β2 appendages crosslink adjacent CHC β-propellers and that the appendage densities are enriched in CCV hexagonal faces. We resolve how adaptor protein 2 and other associated factors in hexagonal faces form an assembly hub with an extensive web of interactions between neighboring β-propellers and propose a structural model that explains how adaptor binding can direct the formation of pentagonal and hexagonal faces.

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Section: Introductionmentioning

confidence: 99%

The structures of natively assembled clathrin-coated vesicles

et al. 2020

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“…Clathrin-mediated vesicle trafficking is a complex machinery in eukaryotes that is involved in most endocytic pathways (1), trafficking from trans-Golgi network (2), trafficking from endosomes (3), and also in the critical function of regenerating synaptic vesicles (4)(5)(6). The two main functions of this machinery are engaging with cargo and membrane and also generating negative curvature on membrane such that the cargo ends up in a vesicle.…”

Section: Introductionmentioning

confidence: 99%

The Structures of Natively Assembled Clathrin Coated Vesicles

Paraan

Mendez

Sharum

et al. 2020

Preprint

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Vesicle trafficking by clathrin coated vesicles (CCVs) is one of the major mechanisms by which proteins and nutrients are absorbed by the cell and transported between organelles. The individual proteins comprising the coated vesicles include clathrin heavy chain, clathrin light chain, and a variety of adaptor protein complexes. Much is known about the structures of the individual CCV components, but data are lacking about the structures of the fully assembled complexes together with membrane and in complex with cargo. Here we determined the structures of natively assembled CCVs in a variety of geometries. We show that the adaptor β2appendages crosslink adjacent CHC β-propellers and that the appendage densities reside almost exclusively in CCV hexagonal faces. We resolve how AP2 and other associated factors in hexagonal faces form an assembly hub with an extensive web of interactions between neighboring β-propellers and propose a structural model that explains how adaptor binding can direct the formation of pentagonal and hexagonal faces.

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“…These adapters can bind directly to cargo proteins and recruit clathrin coat proteins at the same time. Some SV cargoes, such as vGlut1, VAMP2, and Syt1, contain several retrieval motifs that are recognized by multiple different adapter proteins [39]. As the SV membrane is reformed at various rates through different modes depending on neural activity, a “safeguard” system with multiple motifs in individual cargoes definitely help to maintain the exact stoichiometry of the essential SV cargoes required per SV [39].…”

Section: Discussionmentioning

confidence: 99%

SGIP1α functions as a selective endocytic adaptor for the internalization of synaptotagmin 1 at synapses

et al. 2019

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Proper sorting of exocytosed synaptic vesicle (SV) proteins into individual SVs during endocytosis is of the utmost importance for the fidelity of subsequent neurotransmission. Recent studies suggest that each SV protein is sorted into individual SVs by its own dedicated adaptors as well as by association between SV proteins. The SH3-containing GRB2-like protein 3-interacting protein 1 (SGIP1), an ortholog of Fer/Cip4 homology domain-only (FCHo) proteins, contains a μ-homology domain (μHD) and binds AP-2 and Eps15, thus functioning as an endocytic regulator of clathrin-mediated endocytosis (CME). Its longest isoform SGIP1α is predominantly expressed in the brain but the functional significance of SGIP1 in SV recycling remains unknown. Here, we found that SGIP1α, a brain-specific long isoform of SGIP1 binds synaptotagmin1 (Syt1) via its μHD and promotes the internalization of Syt1 on the neuronal surface. The small hairpin RNA (shRNA)-mediated knockdown (KD) of SGIP1α caused selective impairment of Syt1 internalization at hippocampal synapses and it was fully rescued by coexpression of the shRNA-resistant form of SGIP1α in KD neurons. We further found that the μHD of SGIP1α is structurally similar to those of AP-2 and stonin2, and mutations at Trp771 and Lys781, which correspond to Syt1-recognition motifs of AP-2 and stonin2, to Ala bound less efficiently to Syt1 and failed to rescue the endocytic defect of Syt1 caused by KD. Our results indicate that SGIP1α is an endocytic adaptor dedicated to the retrieval of surface-stranded Syt1. Since endocytic sorting of Syt1 is also mediated by the overlapping activities of synaptic vesicle glycoprotein 2A/B (SV2A/B) and stonin2, our results suggest that complementary fail-safe mechanism by these proteins ensures high fidelity of Syt1 retrieval.

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Molecular Signatures Underlying Synaptic Vesicle Cargo Retrieval

Cited by 13 publications

References 124 publications

The structures of natively assembled clathrin-coated vesicles

The structures of natively assembled clathrin-coated vesicles

The Structures of Natively Assembled Clathrin Coated Vesicles

SGIP1α functions as a selective endocytic adaptor for the internalization of synaptotagmin 1 at synapses

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