Edited by Norma M. Allewell 2 The abbreviations used are: IDP, intrinsically disordered protein; IDR intrinsically disordered protein region; PTM, post-translational modification; ER, endoplasmic reticulum; GAP, GTPase-activating protein; ALPS, amphipathic lipid-packing sensor; NSF, N-ethylmaleimide-sensitive factor; SNAP, soluble NSF attachment protein; NTD, N-terminal domain; CTD, C-terminal domain; AH, accessory helix; CH, central helix; SH, Src homology; RIM-BP, RIM-binding protein; Syt1, synaptotagmin-1; MARCKS, membrane-binding region of the myristoylated alanine-rich protein kinase C substrate; CaMKII, calcium/calmodulin-dependent protein kinase II; PSD, postsynaptic density; SV, synaptic vesicle; NAC, non-amyloid-beta-component.The SNARE proteins (for SNAP receptor proteins, where SNAPs are soluble NSF attachment proteins, and NSF is the N-ethylmaleimide-sensitive factor) are a superfamily of small proteins that mediate membrane fusion in all steps of cellular secretory pathways and that constitute the core membrane fusion machinery (30,31). Humans contain 36 different SNARE proteins, which are found attached to membranes, often through a C-terminal transmembrane domain, although attachment via post-translational lipidation also occurs for JBC REVIEWS: Protein disorder in vesicle traffic and release 3326 Figure 2. SNARE proteins constitute a core membrane fusion machinery wherein a disorder-to-order transition is coupled to force transfer that induces membrane fusion. The SNARE proteins associated with synaptic vesicle exocytosis are highlighted here. Initially, syntaxin-1 (red) and SNAP-25 (gray) are anchored to the plasma membrane, whereas synaptobrevin-2 (blue) is anchored to synaptic vesicles. During synaptic vesicle fusion with the plasma membrane, the disordered SNARE motifs of these three proteins assemble into a stable four-helix bundle (with two helices contributed by SNAP-25). Although still incompletely understood, the energy of SNARE complex assembly is thought to drive membrane fusion, as the complex transitions from an initial partially assembled trans-SNARE complex (with SNAREs anchored in opposing membranes), through fusion pore opening, to a final fully assembled cis-SNARE complex (with all three SNAREs now in the plasma membrane). Subsequent to membrane fusion, the cis-SNARE complex is disassembled by NSF in an ATP-dependent fashion.JBC REVIEWS: Protein disorder in vesicle traffic and release 3328