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Gene Review

NSF  -  N-ethylmaleimide-sensitive factor

Homo sapiens

Synonyms: N-ethylmaleimide-sensitive fusion protein, NEM-sensitive fusion protein, SKD2, Vesicle-fusing ATPase, Vesicular-fusion protein NSF
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Disease relevance of NSF

  • Our results show that endosome fusion is not affected by tetanus toxin although cellubrevin is almost completely proteolyzed, suggesting that the function of NSF in endosome fusion does not involve cellubrevin [1].
  • Mast cells, specialized secretory cells that release mediators of inflammatory and allergic reactions in a process of regulated exocytosis, express Syt homologues and SNAREs (Soluble NSF Attachment proteins Receptors), which together with Syt constitute the core complex which mediates exocytotic vesicle docking and fusion [2].
  • These NSF inhibitors are fusion polypeptides composed of an 11 amino acid human immunodeficiency virus transactivating regulatory protein (TAT) domain fused to a 22 amino acid NSF domain [3].
  • Inactivation of NSF blocks the transport of SFV glycoproteins and vesicular stomatitis virus G-glycoprotein from the TGN membranes to the cell surface [4].
  • This research project aimed to determine whether runners with a history of tibial stress fracture (TSF) differ in tibial bone geometry, tibial bone mass, and ground reaction force (GRF) parameters during running from those who have never sustained a stress fracture (NSF) [5].

Psychiatry related information on NSF


High impact information on NSF

  • In this issue of Cell, Matsushita et al. report that in aortic endothelial cells, S-nitrosylation of NSF, an ATPase essential for the activation of the membranefusion machinery, inhibits the exocytosis of Weibel-Palade bodies, secretory granules containing a cocktail of mediators essential to the regulation of vascular vessel tone [10].
  • Oligomeric complexes link Rab5 effectors with NSF and drive membrane fusion via interactions between EEA1 and syntaxin 13 [11].
  • A cell-free system that mimics the reassembly of Golgi stacks at the end of mitosis requires two ATPases, NSF and p97, to rebuild Golgi cisternae [12].
  • The structure suggests several regions responsible for coupling of ATP hydrolysis to structural changes in full-length NSF [13].
  • Formation of the tubule networks requires ATP, cytosol, and the general fusion protein NSF [14].

Chemical compound and disease context of NSF

  • There is growing recognition of the association between the use of gadolinium-containing radiocontrast agents for magnetic resonance imaging and the serious dermal and systemic disease nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis (NFD/NSF) [15].

Biological context of NSF

  • SNARE [soluble NSF (N-ethylmaleimide-sensitive fusion protein) attachment protein receptor] proteins are essential for membrane fusion and are conserved from yeast to humans [16].
  • The presence of both the general transport proteins (NSF and SNAPs) and specific transport proteins (syntaxin 2 and 4) indicates that platelet exocytosis uses a molecular mechanism similar to other secretory cells such as neurons [17].
  • In cells expressing an ATPase-deficient NSF/E329Q mutant that inhibits SNARE complex disassembly, the cycling kinetics of p115-GFP are significantly slower (t1/2 approximately 21 s) [18].
  • RBL-2H3 cells were cotransfected with a plasmid encoding a human growth hormone secretion reporter along with either wild-type NSF or an NSF mutant that lacks ATPase activity [19].
  • These data are consistent with the hypothesis that conformational changes in syntaxin, resulting from protein-protein interactions and ATP hydrolysis by NSF, mediate neurotransmitter release [20].

Anatomical context of NSF


Associations of NSF with chemical compounds

  • The lack of NSF binding, however, resulted in receptors that were endocytosed to a greater extent than wild-type receptors in response to application of AMPA or N-methyl-d-aspartate (NMDA) [24].
  • Furthermore, N-ethylmaleimide treatment abolished the NSF/CD28 interaction completely, and blocked CD28 association with a tyrosine phosphorylated 103 kDa protein in the activated cells [25].
  • Insulin secretion is initiated by ionic events involving membrane depolarization and Ca(2+) entry, whereas exocytic SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins mediate exocytosis itself [26].
  • In this study, NH2- and COOH-terminal truncation mutants of alpha-SNAP were assayed for ability to bind NSF and stimulate its ATPase activity [27].
  • The AMPA-subclass glutamate receptor GluR2 interacts with the membrane-fusion protein NSF in a manner that appears important for receptor-mediated intracellular signalling [28].

Physical interactions of NSF

  • However, NSF action on this syntaxin fragment has no effect on the binding of alpha-SNAP or synaptobrevin [21].
  • Neurosecretion is catalyzed by assembly of a soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE)-complex composed of SNAP-25, synaptobrevin and syntaxin [29].
  • A yeast two-hybrid screen using NSF as bait identified Rab11-FIP3 and the Pak-binding nucleotide exchange factor betaPIX as putative binding partners. betaPIX interacts with recombinant NSF in co-sedimentation assays and the two proteins may be co-immunoprecipitated [30].
  • Mutational analysis of RAMP3, by deletion and point mutations, indicated that the PDZ motif of RAMP3 interacts with NSF to cause the change in trafficking [31].
  • This binding is distinct from other SNAP interactions since no alpha-SNAP or NSF coprecipitated with Gaf-1 [32].

Enzymatic interactions of NSF


Co-localisations of NSF


Regulatory relationships of NSF


Other interactions of NSF


Analytical, diagnostic and therapeutic context of NSF


  1. Cleavage of cellubrevin by tetanus toxin does not affect fusion of early endosomes. Link, E., McMahon, H., Fischer von Mollard, G., Yamasaki, S., Niemann, H., Südhof, T.C., Jahn, R. J. Biol. Chem. (1993) [Pubmed]
  2. Synaptotagmin regulates mast cell functions. Baram, D., Mekori, Y.A., Sagi-Eisenberg, R. Immunol. Rev. (2001) [Pubmed]
  3. A novel class of fusion polypeptides inhibits exocytosis. Matsushita, K., Morrell, C.N., Lowenstein, C.J. Mol. Pharmacol. (2005) [Pubmed]
  4. Inhibition of the membrane fusion machinery prevents exit from the TGN and proteolytic processing by furin. Band, A.M., Määttä, J., Kääriäinen, L., Kuismanen, E. FEBS Lett. (2001) [Pubmed]
  5. Ground reaction forces, bone characteristics, and tibial stress fracture in male runners. Crossley, K., Bennell, K.L., Wrigley, T., Oakes, B.W. Medicine and science in sports and exercise. (1999) [Pubmed]
  6. Early convergence research and education supported by the National Science Foundation. Bainbridge, W.S. Ann. N. Y. Acad. Sci. (2004) [Pubmed]
  7. Cognitive dietary restraint is associated with stress fractures in women runners. Guest, N.S., Barr, S.I. International journal of sport nutrition and exercise metabolism. (2005) [Pubmed]
  8. Teaching engineering ethics using role-playing in a culturally diverse student group. Prince, R.H. Science and engineering ethics. (2006) [Pubmed]
  9. Synaptosomal proteins, beta-soluble N-ethylmaleimide-sensitive factor attachment protein (beta-SNAP), gamma-SNAP and synaptotagmin I in brain of patients with Down syndrome and Alzheimer's disease. Yoo, B.C., Cairns, N., Fountoulakis, M., Lubec, G. Dementia and geriatric cognitive disorders. (2001) [Pubmed]
  10. S-nitrosylation of NSF controls membrane trafficking. Söllner, T.H., Sequeira, S. Cell (2003) [Pubmed]
  11. Oligomeric complexes link Rab5 effectors with NSF and drive membrane fusion via interactions between EEA1 and syntaxin 13. McBride, H.M., Rybin, V., Murphy, C., Giner, A., Teasdale, R., Zerial, M. Cell (1999) [Pubmed]
  12. Syntaxin 5 is a common component of the NSF- and p97-mediated reassembly pathways of Golgi cisternae from mitotic Golgi fragments in vitro. Rabouille, C., Kondo, H., Newman, R., Hui, N., Freemont, P., Warren, G. Cell (1998) [Pubmed]
  13. Crystal structure of the hexamerization domain of N-ethylmaleimide-sensitive fusion protein. Lenzen, C.U., Steinmann, D., Whiteheart, S.W., Weis, W.I. Cell (1998) [Pubmed]
  14. Brefeldin A, a drug that blocks secretion, prevents the assembly of non-clathrin-coated buds on Golgi cisternae. Orci, L., Tagaya, M., Amherdt, M., Perrelet, A., Donaldson, J.G., Lippincott-Schwartz, J., Klausner, R.D., Rothman, J.E. Cell (1991) [Pubmed]
  15. Gadolinium deposition in nephrogenic fibrosing dermopathy. Boyd, A.S., Zic, J.A., Abraham, J.L. J. Am. Acad. Dermatol. (2007) [Pubmed]
  16. Conserved structural features of the synaptic fusion complex: SNARE proteins reclassified as Q- and R-SNAREs. Fasshauer, D., Sutton, R.B., Brunger, A.T., Jahn, R. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  17. Regulated secretion in platelets: identification of elements of the platelet exocytosis machinery. Lemons, P.P., Chen, D., Bernstein, A.M., Bennett, M.K., Whiteheart, S.W. Blood (1997) [Pubmed]
  18. On and off membrane dynamics of the endoplasmic reticulum-golgi tethering factor p115 in vivo. Brandon, E., Szul, T., Alvarez, C., Grabski, R., Benjamin, R., Kawai, R., Sztul, E. Mol. Biol. Cell (2006) [Pubmed]
  19. Mast cell degranulation requires N-ethylmaleimide-sensitive factor-mediated SNARE disassembly. Puri, N., Kruhlak, M.J., Whiteheart, S.W., Roche, P.A. J. Immunol. (2003) [Pubmed]
  20. Distinct domains of syntaxin are required for synaptic vesicle fusion complex formation and dissociation. Kee, Y., Lin, R.C., Hsu, S.C., Scheller, R.H. Neuron (1995) [Pubmed]
  21. The N-ethylmaleimide-sensitive fusion protein and alpha-SNAP induce a conformational change in syntaxin. Hanson, P.I., Otto, H., Barton, N., Jahn, R. J. Biol. Chem. (1995) [Pubmed]
  22. Three-dimensional structure of the amino-terminal domain of syntaxin 6, a SNAP-25 C homolog. Misura, K.M., Bock, J.B., Gonzalez, L.C., Scheller, R.H., Weis, W.I. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  23. Expression of vesicular monoamine transporters, synaptosomal-associated protein 25 and syntaxin1: a signature of human small cell lung carcinoma. Graff, L., Castrop, F., Bauer, M., Höfler, H., Gratzl, M. Cancer Res. (2001) [Pubmed]
  24. Differential roles for NSF and GRIP/ABP in AMPA receptor cycling. Braithwaite, S.P., Xia, H., Malenka, R.C. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  25. CD28 stimulation regulates its association with N-ethylmaleimide-sensitive fusion protein and other proteins involved in vesicle sorting. Heller, M., Watts, J.D., Aebersold, R. Proteomics (2001) [Pubmed]
  26. Synaptosome-associated protein of 25 kilodaltons modulates Kv2.1 voltage-dependent K(+) channels in neuroendocrine islet beta-cells through an interaction with the channel N terminus. MacDonald, P.E., Wang, G., Tsuk, S., Dodo, C., Kang, Y., Tang, L., Wheeler, M.B., Cattral, M.S., Lakey, J.R., Salapatek, A.M., Lotan, I., Gaisano, H.Y. Mol. Endocrinol. (2002) [Pubmed]
  27. Stimulation of NSF ATPase activity by alpha-SNAP is required for SNARE complex disassembly and exocytosis. Barnard, R.J., Morgan, A., Burgoyne, R.D. J. Cell Biol. (1997) [Pubmed]
  28. Synaptic transmission: two players team up for a new tune. Jahn, R. Curr. Biol. (1998) [Pubmed]
  29. Intracellular interaction between syntaxin and Munc 18-1 revealed by fluorescence resonance energy transfer. Yerrapureddy, A., Korte, T., Hollmann, S., Nordhoff, M., Ahnert-Hilger, G., Herrmann, A., Veit, M. Mol. Membr. Biol. (2005) [Pubmed]
  30. Novel putative targets of N-ethylmaleimide sensitive fusion protein (NSF) and alpha/beta soluble NSF attachment proteins (SNAPs) include the Pak-binding nucleotide exchange factor betaPIX. Martin, H.G., Henley, J.M., Meyer, G. J. Cell. Biochem. (2006) [Pubmed]
  31. Novel function for receptor activity-modifying proteins (RAMPs) in post-endocytic receptor trafficking. Bomberger, J.M., Parameswaran, N., Hall, C.S., Aiyar, N., Spielman, W.S. J. Biol. Chem. (2005) [Pubmed]
  32. Gaf-1, a gamma -SNAP-binding protein associated with the mitochondria. Chen, D., Xu, W., He, P., Medrano, E.E., Whiteheart, S.W. J. Biol. Chem. (2001) [Pubmed]
  33. Pctaire1 phosphorylates N-ethylmaleimide-sensitive fusion protein: implications in the regulation of its hexamerization and exocytosis. Liu, Y., Cheng, K., Gong, K., Fu, A.K., Ip, N.Y. J. Biol. Chem. (2006) [Pubmed]
  34. Control of vesicle fusion by a tyrosine phosphatase. Huynh, H., Bottini, N., Williams, S., Cherepanov, V., Musumeci, L., Saito, K., Bruckner, S., Vachon, E., Wang, X., Kruger, J., Chow, C.W., Pellecchia, M., Monosov, E., Greer, P.A., Trimble, W., Downey, G.P., Mustelin, T. Nat. Cell Biol. (2004) [Pubmed]
  35. R-type voltage-gated Ca(2+) channel interacts with synaptic proteins and recruits synaptotagmin to the plasma membrane of Xenopus oocytes. Cohen, R., Atlas, D. Neuroscience (2004) [Pubmed]
  36. Minireview: aquaporin 2 trafficking. Valenti, G., Procino, G., Tamma, G., Carmosino, M., Svelto, M. Endocrinology (2005) [Pubmed]
  37. Target soluble N-ethylmaleimide-sensitive factor attachment protein receptors (t-SNAREs) differently regulate activation and inactivation gating of Kv2.2 and Kv2.1: Implications on pancreatic islet cell Kv channels. Wolf-Goldberg, T., Michaelevski, I., Sheu, L., Gaisano, H.Y., Chikvashvili, D., Lotan, I. Mol. Pharmacol. (2006) [Pubmed]
  38. Role of vesicle-associated membrane protein-2, through Q-soluble N-ethylmaleimide-sensitive factor attachment protein receptor/R-soluble N-ethylmaleimide-sensitive factor attachment protein receptor interaction, in the exocytosis of specific and tertiary granules of human neutrophils. Mollinedo, F., Martín-Martín, B., Calafat, J., Nabokina, S.M., Lazo, P.A. J. Immunol. (2003) [Pubmed]
  39. Differential roles of syntaxin 7 and syntaxin 8 in endosomal trafficking. Prekeris, R., Yang, B., Oorschot, V., Klumperman, J., Scheller, R.H. Mol. Biol. Cell (1999) [Pubmed]
  40. Combinatorial SNARE complexes modulate the secretion of cytoplasmic granules in human neutrophils. Mollinedo, F., Calafat, J., Janssen, H., Martín-Martín, B., Canchado, J., Nabokina, S.M., Gajate, C. J. Immunol. (2006) [Pubmed]
  41. NSF and p97/VCP: similar at first, different at last. Brunger, A.T., DeLaBarre, B. FEBS Lett. (2003) [Pubmed]
  42. Syntaxin 5 interacts with presenilin holoproteins, but not with their N- or C-terminal fragments, and affects beta-amyloid peptide production. Suga, K., Tomiyama, T., Mori, H., Akagawa, K. Biochem. J. (2004) [Pubmed]
  43. Crystal structure of the amino-terminal domain of N-ethylmaleimide-sensitive fusion protein. May, A.P., Misura, K.M., Whiteheart, S.W., Weis, W.I. Nat. Cell Biol. (1999) [Pubmed]
  44. Electron cryomicroscopy structure of N-ethyl maleimide sensitive factor at 11 A resolution. Furst, J., Sutton, R.B., Chen, J., Brunger, A.T., Grigorieff, N. EMBO J. (2003) [Pubmed]
  45. N-Ethylmaleimide-sensitive fusion protein contains high and low affinity ATP-binding sites that are functionally distinct. Matveeva, E.A., He, P., Whiteheart, S.W. J. Biol. Chem. (1997) [Pubmed]
  46. Domain structure of an N-ethylmaleimide-sensitive fusion protein involved in vesicular transport. Tagaya, M., Wilson, D.W., Brunner, M., Arango, N., Rothman, J.E. J. Biol. Chem. (1993) [Pubmed]
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