PI(4,5)P2-dependent regulation of exocytosis by amisyn, the vertebrate-specific competitor of synaptobrevin 2

Ilona Kondratiuk, Shrutee Jakhanwal, Jialin Jin, Udhayabhaskar Sathyanarayanan, Benjamin Kroppen, Ajaybabu V. Pobbati, Anita Krisko, Uri Ashery, Michael Meinecke, Reinhard Jahn, Dirk Fasshauer, Ira Milosevic

Research output: Contribution to journalArticlepeer-review

Abstract

The functions of nervous and neuroendocrine systems rely on fast and tightly regulated release of neurotransmitters stored in secretory vesicles through SNARE-mediated exocytosis. Few proteins, including tomosyn (STXBP5) and amisyn (STXBP6), were proposed to negatively regulate exocytosis. Little is known about amisyn, a 24-kDa brain-enriched protein with a SNARE motif. We report here that full-length amisyn forms a stable SNARE complex with syntaxin-1 and SNAP-25 through its C-terminal SNARE motif and competes with synaptobrevin-2/VAMP2 for the SNAREcomplex assembly. Furthermore, amisyn contains an N-terminal pleckstrin homology domain that mediates its transient association with the plasma membrane of neurosecretory cells by binding to phospholipid PI(4,5)P2. However, unlike synaptrobrevin-2, the SNARE motif of amisyn is not sufficient to account for the role of amisyn in exocytosis: Both the pleckstrin homology domain and the SNARE motif are needed for its inhibitory function. Mechanistically, amisyn interferes with the priming of secretory vesicles and the sizes of releasable vesicle pools, but not vesicle fusion properties. Our biochemical and functional analyses of this vertebrate-specific protein unveil key aspects of negative regulation of exocytosis.

Original languageEnglish
Pages (from-to)13468-13479
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number24
DOIs
StatePublished - 16 Jun 2020

Keywords

  • Autism spectrum disorders
  • Exocytosis inhibition
  • PI(4,5)P2
  • SNARE complex
  • Tomosyn

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