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.2010 Feb;38(Pt 1):209-12.
doi: 10.1042/BST0380209.

Autoinhibition of SNARE complex assembly by a conformational switch represents a conserved feature of syntaxins

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Autoinhibition of SNARE complex assembly by a conformational switch represents a conserved feature of syntaxins

Chris MacDonald et al. Biochem Soc Trans.2010 Feb.

Abstract

Regulation and specificity of membrane trafficking are required to maintain organelle integrity while performing essential cellular transport. Membrane fusion events in all eukaryotic cells are facilitated by the formation of specific SNARE (soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptor) complexes between proteins on opposing lipid bilayers. Although regulation of SNARE complex assembly is not well understood, it is clear that two conserved protein families, the Sx (syntaxin) and the SM (Sec1p/Munc18) proteins, are central to this process. Sxs are a subfamily of SNARE proteins; in addition to the coiled-coil SNARE motif, Sxs possess an N-terminal, autonomously folded, triple-helical (Habc) domain. For some Sxs, it has been demonstrated that this Habc domain exerts an autoinhibitory effect on SNARE complex assembly by making intramolecular contacts with the SNARE motif. SM proteins regulate membrane fusion through interactions with their cognate Sxs. One hypothesis for SM protein function is that they facilitate a switch of the Sx from a closed to an open conformation, thus lifting the inhibitory action of the Habc domain and freeing the SNARE motif to participate in SNARE complexes. However, whether these regulatory mechanisms are conserved throughout the Sx/SM protein families remains contentious as it is not clear whether the closed conformation represents a universal feature of Sxs.

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Figures

Figure 1
Figure 1. Model for the conformational switch of Sxs
In the open conformation (right), the Habc domain (white cylinders) is released from the SNARE motif (grey cylinder) and is therefore free to interact with its cognate SNAREs to form a core complex. In the closed conformation (left), the Habc domain folds back on the SNARE motif, rendering it inaccessible to the cognate SNAREs, thus inhibiting SNARE complex assembly. TMD, transmembrane domain.
Figure 2
Figure 2. SM/Sx-binding sites
Surface representation of the mammalian neuronal SM protein Munc18a (PDB code 3C98). The closed conformation of Sx1a binds in the cleft of the SM protein (mode-1). The N-terminal peptide of the Sx binds in a hydrophobic pocket on the surface (mode-2).
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