Intrinsically disordered proteins in synaptic vesicle trafficking and release

Abstract

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

Deep mutational scanning reveals the structural basis for α-synuclein activity

“…Alternatively, once partially dissociated from the membrane, the C-terminal region of α-synuclein would be poised to aggregate. Membrane binding via the N terminus increases local concentration, facilitating self-association of the hydrophobic NAC region 40 . This is consistent with the propensity of lipid membranes to drive α-synuclein aggregation and amyloid formation 41 .…”

Unroofing site-specific α-synuclein–lipid interactions at the plasma membrane

“…α-Syn is concentrated in presynaptic terminals, where it has been proposed to be involved in synaptic vesicle docking, fusion, clustering, and homeostasis (2,3). As these functions occur on the lipid membrane surface, the ability for α-syn to interact with lipids is essential (4).…”

Untangling the Conformational Polymorphism of Disordered Proteins Associated With Neurodegeneration at the Single-Molecule Level

“…This protein is intrinsically flexible in solution and, similar to other IDPs, acquires structure upon binding to biological binding partners as lipid membranes (Weinreb et al, 1996;Davidson et al, 1998;Eliezer et al, 2001). While αS has been associated with several biological activities, including in regulation of synaptic vesicles pools (Murphy et al, 2000;Cabin et al, 2002), neurotransmitter release (Nemani et al, 2010), SNARE complex assembly (Burré et al, 2010), and vesicle trafficking (Cooper et al, 2006;Snead and Eliezer, 2019), the precise function of this protein remains enigmatic and controversial. αS is the major component of intracellular amyloid deposits known as Lewy bodies and has thus been implicated in the development and pathogenesis of neurodegenerative disorders, such as PD (Polymeropoulos et al, 1997;Spillantini et al, 1998;Goedert, 2001).…”