NSF is a homohexameric AAAATPase involved in membrane fusion. NSF is ubiquitously found in the cytoplasm of eukaryotic cells. It is a central component of the cellular machinery in the transfer of membrane vesicles from one membrane compartment to another. During this process, SNARE proteins on two joining membranes (usually a vesicle and a target membrane such as the plasma membrane) form a tight complex. This aids fusion of the vesicle with the target membrane. It has been proposed that the role of NSF is to undo these SNARE complexes once membrane fusion has occurred, using the hydrolysis of ATP as an energy source, allowing the dissociated SNAREs to be recycled for reuse in further rounds of membrane fusion. This proposal remains controversial, however. Recent work indicates that the ATPase function of NSF does not function in recycling of vesicles but rather functions in the act of fusing vesicles with the plasma membrane.
Because neuronal function depends on the release of neurotransmitters at a synapse — a process in which synaptic vesicles fuse with the presynaptic membrane — NSF is a key synaptic component. Thus, conditional temperature-sensitive mutations in the Drosophila melanogaster gene for NSF lead to a comatose behaviour at the restrictive temperature (and hence the gene is called comatose), presumably because neuronal functions are blocked. In Dictyostelium discoideum amoebae, similar mutations lead to a cessation of cell movement at the restrictive temperature, indicating a role for intracellular membrane transport in migration. Another neuronal role for NSF is indicated by its direct binding to the GluR2 subunit of AMPA type glutamate receptors (which detect the neurotransmitter glutamate). This gives NSF a putative role in delivery and expression of AMPA receptors at the synapse.
NSF was discovered by James Rothman and colleagues in 1987 while at Stanford University; they identified NSF after observing that a cytoplasmic factor, required for membrane fusions, was inactivated by treatment with N-ethylmaleimide. This assay enabled them to purify NSF.
^Hoyle J, Phelan JP, Bermingham N, Fisher EM (November 1996). "Localization of human and mouse N-ethylmaleimide-sensitive factor (NSF) gene: a two-domain member of the AAA family that is involved in membrane fusion". Mamm. Genome7 (11): 850–2. doi:10.1007/s003359900249. PMID8875895.
^Noel J, Ralph GS, Pickard L, Williams J, Molnar E, Uney JB, Collingridge GL, Henley JM (June 1999). "Surface expression of AMPA receptors in hippocampal neurons is regulated by an NSF-dependent mechanism". Neuron23 (2): 365–76. doi:10.1016/S0896-6273(00)80786-2. PMID10399941.
^Glick BS, Rothman JE (1987). "Possible role for fatty acyl-coenzyme A in intracellular protein transport". Nature326 (6110): 309–12. doi:10.1038/326309a0. PMID3821906.
^Hanson, P I; Otto H; Barton N; Jahn R (July 1995). "The N-ethylmaleimide-sensitive fusion protein and alpha-SNAP induce a conformational change in syntaxin". J. Biol. Chem. (UNITED STATES) 270 (28): 16955–61. doi:10.1074/jbc.270.28.16955. ISSN0021-9258. PMID7622514.
Hanson PI, Otto H, Barton N, Jahn R (1995). "The N-ethylmaleimide-sensitive fusion protein and alpha-SNAP induce a conformational change in syntaxin". J. Biol. Chem.270 (28): 16955–61. doi:10.1074/jbc.270.28.16955. PMID7622514.
Püschel AW, O'Connor V, Betz H (1994). "The N-ethylmaleimide-sensitive fusion protein (NSF) is preferentially expressed in the nervous system". FEBS Lett.347 (1): 55–8. doi:10.1016/0014-5793(94)00505-2. PMID8013662.
Hoyle J, Phelan JP, Bermingham N, Fisher EM (1997). "Localization of human and mouse N-ethylmaleimide-sensitive factor (NSF) gene: a two-domain member of the AAA family that is involved in membrane fusion". Mamm. Genome7 (11): 850–2. doi:10.1007/s003359900249. PMID8875895.
Jacobsson G, Meister B (1997). "Molecular components of the exocytotic machinery in the rat pituitary gland". Endocrinology137 (12): 5344–56. doi:10.1210/en.137.12.5344. PMID8940356.
Osten P, Srivastava S, Inman GJ et al. (1998). "The AMPA receptor GluR2 C terminus can mediate a reversible, ATP-dependent interaction with NSF and alpha- and beta-SNAPs". Neuron21 (1): 99–110. doi:10.1016/S0896-6273(00)80518-8. PMID9697855.
McDonald PH, Cote NL, Lin FT et al. (1999). "Identification of NSF as a beta-arrestin1-binding protein. Implications for beta2-adrenergic receptor regulation". J. Biol. Chem.274 (16): 10677–80. doi:10.1074/jbc.274.16.10677. PMID10196135.
Subramaniam VN, Loh E, Horstmann H et al. (2000). "Preferential association of syntaxin 8 with the early endosome". J. Cell. Sci.113 (6): 997–1008. PMID10683148.
Imai C, Sugai T, Iritani S et al. (2001). "A quantitative study on the expression of synapsin II and N-ethylmaleimide-sensitive fusion protein in schizophrenic patients". Neurosci. Lett.305 (3): 185–8. doi:10.1016/S0304-3940(01)01844-4. PMID11403936.
Kittler JT, Rostaing P, Schiavo G et al. (2001). "The subcellular distribution of GABARAP and its ability to interact with NSF suggest a role for this protein in the intracellular transport of GABA(A) receptors". Mol. Cell. Neurosci.18 (1): 13–25. doi:10.1006/mcne.2001.1005. PMID11461150.