Munc18-1 as a key regulator of neurosecretion.
Munc18-1 plays essential roles in neurosecretion by interacting with syntaxin-1 and controlling the formation of the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) complex. At least three important functions of Munc18-1 have been proposed: (i) molecular chaperone of syntaxin-1 for appropriate localization and expression of syntaxin-1, (ii) priming/stimulation of the SNARE-mediated membrane fusion, and (iii) docking of large dense-core vesicles to the plasma membrane. Similarly, at least two different binding modes have been proposed for the interaction between Munc18-1 and syntaxin-1: (i) binary binding to a 'closed' conformation of syntaxin-1, and (ii) binding to the N-terminal peptide of syntaxin-1, which is thought to enable an interaction with the quaternary SNARE complex and/or further stabilize the binary interaction between Munc18-1 and closed syntaxin-1. Recent structural analyses have identified critical Munc18-1 residues implicated in these different modes of binding. These have recently been tested functionally in rescue experiments using Munc18-1 null neurons, chromaffin cells and Munc18-1/-2 knockdown PC12 cells, allowing remarkable progress to be made in the structural/functional understanding of Munc18-1. In this review, we summarize these recent advances and attempt to propose an updated model of the pleiotropic functions of Munc18-1 in neuroexocytosis.
Han
Gayoung A
GA
Division of Fundamental Neurobiology, University Health Network, Toronto, Ontario, Canada.
Malintan
Nancy T
NT
Collins
Brett M
BM
Meunier
Frederic A
FA
Sugita
Shuzo
S
D000818:Animals; D005089:Exocytosis / Q000235:genetics / Q000502:physiology; D006801:Humans; D051938:Munc18 Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D009489:Neurosecretion / Q000235:genetics* / Q000502:physiology*; D011485:Protein Binding; D011487:Protein Conformation; D050600:SNARE Proteins / Q000235:genetics / Q000502:physiology; D050827:Syntaxin 1 / Q000235:genetics / Q000502:physiology
D051938:Munc18 Proteins; D050600:SNARE Proteins; D050827:Syntaxin 1