Possible roles for Munc18-1 domain 3a and Syntaxin1 N-peptide and C-terminal anchor in SNARE complex formation

Proc Natl Acad Sci U S A. 2011 Jan 18;108(3):1040-5. doi: 10.1073/pnas.0914906108. Epub 2010 Dec 30.

Abstract

Munc18-1 and Syntaxin1 are essential proteins for SNARE-mediated neurotransmission. Munc18-1 participates in synaptic vesicle fusion via dual roles: as a docking/chaperone protein by binding closed Syntaxin1, and as a fusion protein that binds SNARE complexes in a Syntaxin1 N-peptide dependent manner. The two roles are associated with a closed-open Syntaxin1 conformational transition. Here, we show that Syntaxin N-peptide binding to Munc18-1 is not highly selective, suggesting that other parts of the SNARE complex are involved in binding to Munc18-1. We also find that Syntaxin1, with an N peptide and a physically anchored C terminus, binds to Munc18-1 and that this complex can participate in SNARE complex formation. We report a Munc18-1-N-peptide crystal structure that, together with other data, reveals how Munc18-1 might transit from a conformation that binds closed Syntaxin1 to one that may be compatible with binding open Syntaxin1 and SNARE complexes. Our results suggest the possibility that structural transitions occur in both Munc18-1 and Syntaxin1 during their binary interaction. We hypothesize that Munc18-1 domain 3a undergoes a conformational change that may allow coiled-coil interactions with SNARE complexes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Circular Dichroism
  • Crystallography
  • Models, Molecular*
  • Molecular Sequence Data
  • Multiprotein Complexes / metabolism*
  • Munc18 Proteins / chemistry
  • Munc18 Proteins / metabolism*
  • Protein Binding
  • Protein Conformation*
  • SNARE Proteins / metabolism*
  • Sequence Alignment
  • Synaptic Transmission / physiology*
  • Syntaxin 1 / metabolism*

Substances

  • Multiprotein Complexes
  • Munc18 Proteins
  • SNARE Proteins
  • Syntaxin 1

Associated data

  • PDB/3PUJ
  • PDB/3PUK