N-ethylmaleimide sensitive fusion protein

N-ethylmaleimide-sensitive factor
PDB rendering based on 1d2n.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1d2n​, 1nsf​, 1qcs​, 1qdn​
Identifiers
Symbols	NSF ; SKD2
External IDs	OMIM: 601633 MGI: 104560 HomoloGene: 4502 GeneCards: NSF Gene
EC number	3.6.4.6
Gene ontology Molecular function • protein binding • ATP binding • ATPase activity • syntaxin-1 binding • Rab GTPase binding • protein kinase binding • PDZ domain binding • protein complex binding • ATPase activity, coupled • metal ion binding Cellular component • cytoplasm • lysosomal membrane • Golgi stack • cytosol • plasma membrane • postsynaptic density • dendritic shaft • myelin sheath • extracellular exosome Biological process • positive regulation of receptor recycling • potassium ion transport • intracellular protein transport • exocytosis • intra-Golgi vesicle-mediated transport • synaptic transmission • metabolic process • vesicle-mediated transport • regulation of exocytosis • Golgi to plasma membrane protein transport • plasma membrane fusion • positive regulation of protein catabolic process • Golgi vesicle docking Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	4905	18195
Ensembl	ENSG00000073969	ENSMUSG00000034187
UniProt	P46459	P46460
RefSeq (mRNA)	NM_006178	NM_008740
RefSeq (protein)	NP_006169	NP_032766
Location (UCSC)	Chr 17: 46.59 – 46.76 Mb	Chr 11: 103.82 – 103.95 Mb
PubMed search

N-ethylmaleimide-sensitive factor, also known as NSF or N-ethylmaleimide sensitive fusion proteins, is an enzyme which in humans is encoded by the NSF gene.^[1][2][3]

Function

NSF is a homohexameric AAA ATPase 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]

References

1. "Entrez Gene: NSF N-ethylmaleimide-sensitive factor".
2. Wilson DW, Whiteheart SW, Wiedmann M, Brunner M, Rothman JE (May 1992). "A multisubunit particle implicated in membrane fusion". The Journal of Cell Biology 117 (3): 531–8. doi:10.1083/jcb.117.3.531. PMC 2289450. PMID 1315316.
3. 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. PMID 8875895.
4. Furst J, Sutton RB, Chen J, Brunger AT, Grigorieff N (Sep 2003). "Electron cryomicroscopy structure of N-ethyl maleimide sensitive factor at 11 A resolution". The EMBO Journal 22 (17): 4365–74. doi:10.1093/emboj/cdg420. PMC 202363. PMID 12941689.
5. Alberts, Bruce (2008). Molecular biology of the cell. Garland Science. ISBN 978-0-8153-4105-5.
6. Kuner T, Li Y, Gee KR, Bonewald LF, Augustine GJ (Jan 2008). "Photolysis of a caged peptide reveals rapid action of N-ethylmaleimide sensitive factor before neurotransmitter release". Proceedings of the National Academy of Sciences of the United States of America 105 (1): 347–52. doi:10.1073/pnas.0707197105. PMC 2224215. PMID 18172208.
7. 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. PMID 10399941.
8. 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. PMID 3821906.
9. Barnard RJ, Morgan A, Burgoyne RD (Nov 1997). "Stimulation of NSF ATPase activity by alpha-SNAP is required for SNARE complex disassembly and exocytosis". The Journal of Cell Biology 139 (4): 875–83. doi:10.1083/jcb.139.4.875. PMC 2139964. PMID 9362506.
10. 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. PMID 7622514.

Further reading

• Wilson DW, Whiteheart SW, Wiedmann M, Brunner M, Rothman JE (May 1992). "A multisubunit particle implicated in membrane fusion". The Journal of Cell Biology 117 (3): 531–8. doi:10.1083/jcb.117.3.531. PMC 2289450. PMID 1315316.
• 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. PMID 7622514.
• 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. PMID 8013662.
• Whiteheart SW, Rossnagel K, Buhrow SA, Brunner M, Jaenicke R, Rothman JE (Aug 1994). "N-ethylmaleimide-sensitive fusion protein: a trimeric ATPase whose hydrolysis of ATP is required for membrane fusion". The Journal of Cell Biology 126 (4): 945–54. doi:10.1083/jcb.126.4.945. PMC 2120109. PMID 8051214.
• Nagahama M, Orci L, Ravazzola M, Amherdt M, Lacomis L, Tempst P, Rothman JE, Söllner TH (May 1996). "A v-SNARE implicated in intra-Golgi transport". The Journal of Cell Biology 133 (3): 507–16. doi:10.1083/jcb.133.3.507. PMC 2120813. PMID 8636227.
• 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. PMID 8875895.
• 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. PMID 8940356.
• Timmers KI, Clark AE, Omatsu-Kanbe M, Whiteheart SW, Bennett MK, Holman GD, Cushman SW (Dec 1996). "Identification of SNAP receptors in rat adipose cell membrane fractions and in SNARE complexes co-immunoprecipitated with epitope-tagged N-ethylmaleimide-sensitive fusion protein". The Biochemical Journal 320 (2): 429–36. doi:10.1042/bj3200429. PMC 1217948. PMID 8973549.
• 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. PMID 9286697.
• 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. PMID 9325254.
• 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. PMID 9349823.
• Barnard RJ, Morgan A, Burgoyne RD (Nov 1997). "Stimulation of NSF ATPase activity by alpha-SNAP is required for SNARE complex disassembly and exocytosis". The Journal of Cell Biology 139 (4): 875–83. doi:10.1083/jcb.139.4.875. PMC 2139964. PMID 9362506.
• 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. PMID 9697855.
• 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. PMID 10196135.
• 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. PMID 10683148.
• Sagiv Y, Legesse-Miller A, Porat A, Elazar Z (Apr 2000). "GATE-16, a membrane transport modulator, interacts with NSF and the Golgi v-SNARE GOS-28". The EMBO Journal 19 (7): 1494–504. doi:10.1093/emboj/19.7.1494. PMC 310219. PMID 10747018.
• 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. PMID 10903204.
• Michaut M, Tomes CN, De Blas G, Yunes R, Mayorga LS (Aug 2000). "Calcium-triggered acrosomal exocytosis in human spermatozoa requires the coordinated activation of Rab3A and N-ethylmaleimide-sensitive factor". Proceedings of the National Academy of Sciences of the United States of America 97 (18): 9996–10001. doi:10.1073/pnas.180206197. PMC 27650. PMID 10954749.
• 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. PMID 11403936.
• 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. PMID 11461150.