TY - JOUR

T1 - Vesicle uncoating regulated by SH3-SH3 domain-mediated complex formation between endophilin and intersectin at synapses

AU - Pechstein, Arndt

AU - Gerth, Fabian

AU - Milosevic, Ira

AU - Jäpel, Maria

AU - Eichhorn-Grünig, Marielle

AU - Vorontsova, Olga

AU - Bacetic, Jelena

AU - Maritzen, Tanja

AU - Shupliakov, Oleg

AU - Freund, Christian

AU - Haucke, Volker

PY - 2015/2/1

Y1 - 2015/2/1

N2 - Neurotransmission involves the exo-endocytic cycling of synaptic vesicle (SV) membranes. Endocytic membrane retrieval and clathrin-mediated SV reformation require curvature-sensing and membrane-bending BAR domain proteins such as endophilin A. While their ability to sense and stabilize curved membranes facilitates membrane recruitment of BAR domain proteins, the precise mechanisms by which they are targeted to specific sites of SV recycling has remained unclear. Here, we demonstrate that the multi-domain scaffold intersectin 1 directly associates with endophilin A to facilitate vesicle uncoating at synapses. Knockout mice deficient in intersectin 1 accumulate clathrin-coated vesicles at synapses, a phenotype akin to loss of endophilin function. Intersectin 1/endophilin A1 complex formation is mediated by direct binding of the SH3B domain of intersectin to a non-canonical site on the SH3 domain of endophilin A1. Consistent with this, intersectin-binding defective mutant endophilin A1 fails to rescue clathrin accumulation at neuronal synapses derived from endophilin A1-3 triple knockout (TKO) mice. Our data support a model in which intersectin aids endophilin A recruitment to sites of clathrin-mediated SV recycling, thereby facilitating vesicle uncoating. Synopsis Neurotransmission requires endocytic membrane retrieval and clathrin-mediated reformation of synaptic vesicles. This study shows that intersectin 1 directly associates with the BAR domain protein endophilin to facilitate vesicle uncoating at synapses. Intersectin 1 knockout mice accumulate clathrin-coated vesicles akin to endophilin A loss. Intersectin via its SH3B domain directly binds to endophilin A. Intersectin binding is required for endophilin function in vesicle uncoating. Neurotransmission requires endocytic membrane retrieval and clathrin-mediated reformation of synaptic vesicles. This study shows that intersectin 1 directly associates with the BAR domain protein endophilin to facilitate vesicle uncoating at synapses.

AB - Neurotransmission involves the exo-endocytic cycling of synaptic vesicle (SV) membranes. Endocytic membrane retrieval and clathrin-mediated SV reformation require curvature-sensing and membrane-bending BAR domain proteins such as endophilin A. While their ability to sense and stabilize curved membranes facilitates membrane recruitment of BAR domain proteins, the precise mechanisms by which they are targeted to specific sites of SV recycling has remained unclear. Here, we demonstrate that the multi-domain scaffold intersectin 1 directly associates with endophilin A to facilitate vesicle uncoating at synapses. Knockout mice deficient in intersectin 1 accumulate clathrin-coated vesicles at synapses, a phenotype akin to loss of endophilin function. Intersectin 1/endophilin A1 complex formation is mediated by direct binding of the SH3B domain of intersectin to a non-canonical site on the SH3 domain of endophilin A1. Consistent with this, intersectin-binding defective mutant endophilin A1 fails to rescue clathrin accumulation at neuronal synapses derived from endophilin A1-3 triple knockout (TKO) mice. Our data support a model in which intersectin aids endophilin A recruitment to sites of clathrin-mediated SV recycling, thereby facilitating vesicle uncoating. Synopsis Neurotransmission requires endocytic membrane retrieval and clathrin-mediated reformation of synaptic vesicles. This study shows that intersectin 1 directly associates with the BAR domain protein endophilin to facilitate vesicle uncoating at synapses. Intersectin 1 knockout mice accumulate clathrin-coated vesicles akin to endophilin A loss. Intersectin via its SH3B domain directly binds to endophilin A. Intersectin binding is required for endophilin function in vesicle uncoating. Neurotransmission requires endocytic membrane retrieval and clathrin-mediated reformation of synaptic vesicles. This study shows that intersectin 1 directly associates with the BAR domain protein endophilin to facilitate vesicle uncoating at synapses.

KW - endophilin

KW - intersectin

KW - neurotransmission

KW - SH3 domains

KW - synaptic vesicle recycling

UR - http://www.scopus.com/inward/record.url?scp=84961288615&partnerID=8YFLogxK

U2 - 10.15252/embr.201439260

DO - 10.15252/embr.201439260

M3 - Article

C2 - 25520322

AN - SCOPUS:84961288615

VL - 16

SP - 232

EP - 239

JO - EMBO Reports

JF - EMBO Reports

SN - 1469-221X

IS - 2

ER -