Review: Progresses in understanding N‐ethylmaleimide sensitive factor (NSF) mediated disassembly of SNARE complexes

Abstract

N-ethylmaleimide sensitive factor (NSF) is a key protein of intracellular membrane traffic. NSF is a highly conserved protein belonging to the ATPases associated with other activities (AAA+ proteins). AAA+ share common domains and all transduce ATP hydrolysis into major conformational movements that are used to carry out conformational work on client proteins. Together with its cofactor SNAP, NSF is specialized on disassembling highly stable SNARE complexes that form after each membrane fusion event. Although essential for all eukaryotic cells, however, the details of this reaction have long been enigmatic. Recently, major progress has been made in both elucidating the structure of NSF/SNARE complexes and in understanding the reaction mechanism. Advances in both cryo EM and single molecule measurements suggest that NSF, together with its cofactor SNAP, imposes a tight grip on the SNARE complex. After ATP hydrolysis and phosphate release, it then builds up mechanical tension that is ultimately used to rip apart the SNAREs in a single burst. Because the AAA domains are extremely well-conserved, the molecular mechanism elucidated for NSF is presumably shared by many other AAA+ ATPases. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 518-531, 2016.

Membrane Fusion Involved in Neurotransmission: Glimpse from Electron Microscope and Molecular Simulation

“…Active zones of synaptic plasma membranes are known to concentrate the components that drive membrane fusion, such as the SNAREs, Munc 18-1, Munc 13-1 and small-head group lipids (e.g., diacyglycerol and PIP2), while the participation and characteristic of these macromolecular complexes are still not fully understood (Rizo and Xu, 2015; Ryu et al, 2016; Wickner and Rizo, 2017). Strikingly, current experimental techniques do not achieve a resolution better than ms/μs in time, and neuronal membrane fusion normally occurs at ms timescale (Diao et al, 2012).…”

The Multifaceted Role of SNARE Proteins in Membrane Fusion

“…For more information on SNARE assembly and disassembly aided by regulatory and tethering proteins see Baker and Hughson (2016) and Ryu et al (2016). Despite the considerable progress in understanding the intracellular fusion events which involve a variety of proteins apart from the core SNARE complex, a unified picture describing the regulatory network at different levels in SNARE-mediated vesicle fusion is still missing.…”

GPCR Signaling and Trafficking: The Long and Short of It

“…One possibility is that SNX27 is substituted for by another PDZ-adaptor protein. The N -ethylmaleimide-sensitive factor (NSF), for example, an ATPase which usually functions to drive the disassembly of SNARE fusion complexes [69], has been previously implicated in the endosome-plasma membrane recycling of β 2 AR [70]. Moreover, NSF contains a PDZ-domain assuming the recognition sequence of [D/E]-[S/T]-[L/V]-x that would accommodate indiscriminant binding to either native (ETVM) or mutant (ETVA) PTHR-PDZ ligands, a position later substantiated by coimmunoprecipitation experiments in the same study [63].…”