Regulation of synaptic vesicle recycling by complex formation between intersectin 1 and the clathrin adaptor complex AP2

Arndt Pechstein, Jelena Bacetic, Ardeschir Vahedi-Faridi, Kira Gromova, Anna Sundborger, Nikolay Tomlin, Georg Krainer, Olga Vorontsova, Johannes G. Schäfer, Simen G. Owe, Michael A. Cousin, Wolfram Saenger, Oleg Shupliakov, Volker Haucke

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Clathrin-mediated synaptic vesicle (SV) recycling involves the spatiotemporally controlled assembly of clathrin coat components at phosphatidylinositiol (4, 5)-bisphosphate [PI(4,5)P2]-enriched membrane sites within the periactive zone. Such spatiotemporal control is needed to coordinate SV cargo sorting with clathrin/AP2 recruitment and to restrain membrane fission and synaptojanin-mediated uncoating until membrane deformation and clathrin coat assembly are completed. The molecular events underlying these control-mechanisms are unknown. Here we showthat the endocytic SH3 domain-containing accessory protein intersectin 1 scaffolds the endocytic process by directly associating with the clathrin adaptor AP2. Acute perturbation of the intersectin 1-AP2 interaction in lamprey synapses in situ inhibits the onset of SV recycling. Structurally, complex formation can be attributed to the direct association of hydrophobic peptides within the intersectin 1 SH3A-B linker region with the "side sites" of the AP2 α- and β-appendage domains. AP2 appendage association of the SH3A-B linker region inhibits binding of the inositol phosphatase synaptojanin 1 to intersectin 1. These data identify the intersectin-AP2 complex as an important regulator of clathrin-mediated SV recycling in synapses.

Original languageEnglish (US)
Pages (from-to)4206-4211
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number9
DOIs
StatePublished - Mar 2 2010
Externally publishedYes

Keywords

  • Appendage
  • Endocytosis
  • Scaffolding proteins
  • Synapse
  • Synaptojanin

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