{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNSF (N‐ethylmaleimide–sensitive factor) is a highly conserved AAA+ ATPase that plays a central role in intracellular vesicle trafficking by catalyzing the disassembly of SNARE complexes. This process is essential for “resetting” the fusion machinery after vesicle–membrane fusion, thereby enabling multiple rounds of exocytosis. Structural and kinetic analyses suggest that NSF operates via a processive unwinding mechanism that consumes ATP to fully disassemble these four‐stranded helical bundles, ensuring efficient membrane fusion and vesicular recycling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn several systems NSF activity is tightly regulated through post‐translational modifications. Nitric oxide (NO) can S–nitrosylate critical cysteine residues on NSF, thereby inhibiting its ability to disassemble SNARE complexes; this inhibition, however, is reversible by the denitrosylating enzyme thioredoxin (TRX1), which restores NSF function and rescues exocytosis. In addition, phosphorylation events—such as those mediated by kinases like Pctaire1—affect NSF oligomerization and activity, whereas dephosphorylation by phosphatases like PTP1B is required for its proper engagement during processes such as the acrosome reaction in sperm."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNSF’s function is also crucial in cell‐specific contexts. In neurons, for example, NSF binding to AMPA receptor subunits (such as GluR2) supports the surface expression and regulated cycling of these receptors, which is vital for maintaining synaptic strength and plasticity. Similarly, in cardiac myocytes, NSF interactions with receptors like the β2 adrenoceptor modulate receptor internalization, recycling, and even downstream G protein signaling specificity. In mast cells, dominant–negative NSF mutants that lack ATPase activity block SNARE complex disassembly and significantly inhibit regulated degranulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, NSF function may vary with cellular context. For instance, in macrophages examining phagosome–endosome fusion, certain vesicular compartments can fuse efficiently in an NSF–independent manner under specific conditions, underscoring a context–dependent regulatory role. Clinically, de novo mutations in NSF have been associated with severe early–onset epileptic encephalopathy, implicating aberrant NSF function in neurological disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Steven P Braithwaite, Houhui Xia, Robert C Malenka "}, {"type": "b", "children": [{"type": "t", "text": "Differential roles for NSF and GRIP/ABP in AMPA receptor cycling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.102156099"}], "href": "https://doi.org/10.1073/pnas.102156099"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12011465"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12011465"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Kathrin Landgraf, Frank Bollig, Mark-Oliver Trowe, et al. 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