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A dual mechanism controlling the localization and function of exocytic v-SNAREs.

SNARE [soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein receptor] proteins are essential for membrane fusion but their regulation is not yet fully understood. We have previously shown that the amino-terminal Longin domain of the v-SNARE TI-VAMP (tetanus neurotoxin-insensitive vesicle-associated membrane protein)/VAMP7 plays an inhibitory role in neurite outgrowth. The goal of this study was to investigate the regulation of TI-VAMP as a model of v-SNARE regulation. We show here that the Longin domain (LD) plays a dual role. First, it negatively regulates the ability of TI-VAMP and of a Longin/Synaptobrevin chimera to participate in SNARE complexes. Second, it interacts with the adaptor complex AP-3 and this interaction targets TI-VAMP to late endosomes. Accordingly, in mocha cells lacking AP-3 delta, TI-VAMP is retained in an early endosomal compartment. Furthermore, TI-VAMPc, an isoform of TI-VAMP lacking part of the LD, does not interact with AP-3, and therefore is not targeted to late endosomes; however, this shorter LD still inhibits SNARE-complex formation. These findings support a mechanism controlling both localization and function of TI-VAMP through the LD and clathrin adaptors. Moreover, they point to the amino-terminal domains of SNARE proteins as multifunctional modules responsible for the fine tuning of SNARE function.

Pubmed ID: 12853575


  • Martinez-Arca S
  • Rudge R
  • Vacca M
  • Raposo G
  • Camonis J
  • Proux-Gillardeaux V
  • Daviet L
  • Formstecher E
  • Hamburger A
  • Filippini F
  • D'Esposito M
  • Galli T


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

July 22, 2003

Associated Grants


Mesh Terms

  • Adaptor Protein Complex 3
  • Animals
  • Binding Sites
  • Cell Line
  • DNA-Binding Proteins
  • Dogs
  • Exocytosis
  • HeLa Cells
  • Humans
  • Membrane Proteins
  • Molecular Sequence Data
  • Peptide Fragments
  • R-SNARE Proteins
  • SNARE Proteins
  • Subcellular Fractions
  • Transcription Factors
  • Two-Hybrid System Techniques
  • Vesicular Transport Proteins