N-ethylmaleimide-sensitive factor, also known as NSF or N-ethylmaleimide sensitive fusion proteins, is an enzyme which in humans is encoded by the NSFgene.[1][2][3]
NSF is a homohexameric AAAATPase involved in membrane fusion.[4] 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.[5] 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.[6]
SNARE hypothesis
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.[7]
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.[8]
Interactions
N-ethylmaleimide sensitive fusion protein has been shown to interact with NAPA.[9][10]
↑Hoyle J, Phelan JP, Bermingham N, Fisher EM (Nov 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". Mammalian Genome. 7 (11): 850–2. doi:10.1007/s003359900249. PMID8875895.
↑Noel J, Ralph GS, Pickard L, Williams J, Molnar E, Uney JB, Collingridge GL, Henley JM (Jun 1999). "Surface expression of AMPA receptors in hippocampal neurons is regulated by an NSF-dependent mechanism". Neuron. 23 (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". Nature. 326 (6110): 309–12. doi:10.1038/326309a0. PMID3821906.
↑Hanson PI, Otto H, Barton N, Jahn R (Jul 1995). "The N-ethylmaleimide-sensitive fusion protein and alpha-SNAP induce a conformational change in syntaxin". The Journal of Biological Chemistry. 270 (28): 16955–61. doi:10.1074/jbc.270.28.16955. PMID7622514.
Hanson PI, Otto H, Barton N, Jahn R (Jul 1995). "The N-ethylmaleimide-sensitive fusion protein and alpha-SNAP induce a conformational change in syntaxin". The Journal of Biological Chemistry. 270 (28): 16955–61. doi:10.1074/jbc.270.28.16955. PMID7622514.
Püschel AW, O'Connor V, Betz H (Jun 1994). "The N-ethylmaleimide-sensitive fusion protein (NSF) is preferentially expressed in the nervous system". FEBS Letters. 347 (1): 55–8. doi:10.1016/0014-5793(94)00505-2. PMID8013662.
Hoyle J, Phelan JP, Bermingham N, Fisher EM (Nov 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". Mammalian Genome. 7 (11): 850–2. doi:10.1007/s003359900249. PMID8875895.
Jacobsson G, Meister B (Dec 1996). "Molecular components of the exocytotic machinery in the rat pituitary gland". Endocrinology. 137 (12): 5344–56. doi:10.1210/en.137.12.5344. PMID8940356.
Germain-Lee EL, Obie C, Valle D (Aug 1997). "NVL: a new member of the AAA family of ATPases localized to the nucleus". Genomics. 44 (1): 22–34. doi:10.1006/geno.1997.4856. PMID9286697.
Subramaniam VN, Loh E, Hong W (Oct 1997). "N-Ethylmaleimide-sensitive factor (NSF) and alpha-soluble NSF attachment proteins (SNAP) mediate dissociation of GS28-syntaxin 5 Golgi SNAP receptors (SNARE) complex". The Journal of Biological Chemistry. 272 (41): 25441–4. doi:10.1074/jbc.272.41.25441. PMID9325254.
Lowe SL, Peter F, Subramaniam VN, Wong SH, Hong W (Oct 1997). "A SNARE involved in protein transport through the Golgi apparatus". Nature. 389 (6653): 881–4. doi:10.1038/39923. PMID9349823.
Osten P, Srivastava S, Inman GJ, Vilim FS, Khatri L, Lee LM, States BA, Einheber S, Milner TA, Hanson PI, Ziff EB (Jul 1998). "The AMPA receptor GluR2 C terminus can mediate a reversible, ATP-dependent interaction with NSF and alpha- and beta-SNAPs". Neuron. 21 (1): 99–110. doi:10.1016/S0896-6273(00)80518-8. PMID9697855.
McDonald PH, Cote NL, Lin FT, Premont RT, Pitcher JA, Lefkowitz RJ (Apr 1999). "Identification of NSF as a beta-arrestin1-binding protein. Implications for beta2-adrenergic receptor regulation". The Journal of Biological Chemistry. 274 (16): 10677–80. doi:10.1074/jbc.274.16.10677. PMID10196135.
Subramaniam VN, Loh E, Horstmann H, Habermann A, Xu Y, Coe J, Griffiths G, Hong W (Mar 2000). "Preferential association of syntaxin 8 with the early endosome". Journal of Cell Science. 113 (6): 997–1008. PMID10683148.
Allan BB, Moyer BD, Balch WE (Jul 2000). "Rab1 recruitment of p115 into a cis-SNARE complex: programming budding COPII vesicles for fusion". Science. 289 (5478): 444–8. doi:10.1126/science.289.5478.444. PMID10903204.
Imai C, Sugai T, Iritani S, Niizato K, Nakamura R, Makifuchi T, Kakita A, Takahashi H, Nawa H (Jun 2001). "A quantitative study on the expression of synapsin II and N-ethylmaleimide-sensitive fusion protein in schizophrenic patients". Neuroscience Letters. 305 (3): 185–8. doi:10.1016/S0304-3940(01)01844-4. PMID11403936.
Kittler JT, Rostaing P, Schiavo G, Fritschy JM, Olsen R, Triller A, Moss SJ (Jul 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". Molecular and Cellular Neurosciences. 18 (1): 13–25. doi:10.1006/mcne.2001.1005. PMID11461150.
