Abstract
Membrane fusion is essential for human health, playing a vital role in processes as diverse as neurotransmission and blood glucose control. Two protein families are key: (1) the Sec1p/Munc18 (SM) and (2) the soluble N-ethylmaleimide-sensitive attachment protein receptor (SNARE) proteins. Whilst the essential nature of these proteins is irrefutable, their exact regulatory roles in membrane fusion remain controversial. In particular, whether SM proteins promote and/or inhibit the SNARE-complex formation required for membrane fusion is not resolved. Crystal structures of SM proteins alone and in complex with their cognate SNARE proteins have provided some insight, however, these structures lack the transmembrane spanning regions of the SNARE proteins and may not accurately reflect the native state. Here, we review the literature surrounding the regulatory role of mammalian Munc18 SM proteins required for exocytosis in eukaryotes. Our analysis suggests that the conflicting roles reported for these SM proteins may reflect differences in experimental design. SNARE proteins appear to require C-terminal immobilization or anchoring, for example through a transmembrane domain, to form a functional fusion complex in the presence of Munc18 proteins.
Highlights
Membrane fusion in eukaryotes is essential for many physiological functions, from blood glucose control to neurotransmission
Understanding the molecular basis of membrane fusion mediated by soluble N-ethylmaleimidesensitive attachment protein receptor (SNARE) and SM proteins is highly relevant to health and disease
The SNAREs involved in exocytosis are the t-SNAREs syntaxin 1a (Sx1a) and the synaptosomal-associated protein 25, and the vSNARE vesicle-associated membrane protein 2 (VAMP2 or synaptobrevin)
Summary
Membrane fusion in eukaryotes is essential for many physiological functions, from blood glucose control to neurotransmission. SNARE-complex assembly, and attempt to reconcile the Structural studies on neuronal SM proteins have suggested conflicting roles of SM proteins that have been observed This that Munc18a plays a negative regulatory role in membrane review will focus on the three mammalian SM proteins fusion by binding to closed Sx1a, thereby preventing SNARE-. N-terminal region (the N-peptide, 1–29 residues) connected to Whether SM proteins limit or promote SNARE-complex a domain containing three -helices (Habc) linked to a single formation and subsequent membrane fusion may be a SNARE helix (H3) followed by a transmembrane domain consequence of preferential interaction with open or closed (TMD) (Fig. 1a) (Lerman et al, 2000). Other studies have drawn another conclusion: that Munc binds open Sx
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