{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nHuman cytosolic sialidase NEU2 is a glycohydrolytic enzyme that catalyzes the removal of terminal sialic acid residues from glycoproteins, glycolipids, and gangliosides. Structural studies reveal that NEU2 adopts the classical six‐blade β‐propeller architecture with a shallow catalytic crevice where key residues—including a conserved arginine triad and Tyr334—play essential roles in substrate positioning and transition state stabilization. Detailed kinetic and substrate‐specificity analyses, supported by molecular docking and mutational studies, have further delineated the dynamic network of interactions underpinning the recognition of diverse sialosides and the influence of temperature‐dependent conformational changes on enzymatic activity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its well‐characterized catalytic mechanism, NEU2 influences diverse physiological processes. A naturally occurring nonsynonymous SNP (R41Q) in NEU2 has been shown to reduce its intrinsic activity and increase its binding affinity for oseltamivir carboxylate, which may have clinical implications in drug-induced neuropsychiatric reactions. Moreover, NEU2 expression is generally low in many tissues yet is detectable in the placenta and testis and appears to contribute to cell survival and motility in certain cancer cells – regulated in part by transcription factors such as Runx2 and Sp3. NEU2 also participates in receptor-mediated signaling in platelets through desialylation after glycoprotein Ibα clustering and collaborates with cytosolic β-glycosidase GBA3 to promote the catabolism of sialylated free N-glycans."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of disease and membrane dynamics, NEU2 has emerged as a modulator of cellular differentiation and cancer stem cell properties. In pancreatic cancer sphere-forming cells, overexpression of NEU2 triggers desialylation of key signaling molecules such as Sonic Hedgehog, thereby dampening Hedgehog pathway activity, reducing stemness markers, and promoting apoptosis. Similarly, its absent or diminished expression in rhabdomyosarcoma cells is correlated with impaired myogenic differentiation. Additionally, by altering the sialylation status of gangliosides in glycosphingolipid-enriched microdomains, NEU2 activity reshapes membrane headgroup organization and potentially influences receptor-mediated signal transduction."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Leonard M G Chavas, Cristina Tringali, Paola Fusi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Crystal structure of the human cytosolic sialidase Neu2. Evidence for the dynamic nature of substrate recognition."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M411506200"}], "href": "https://doi.org/10.1074/jbc.M411506200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15501818"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15501818"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Cristina Tringali, Nadia Papini, Paola Fusi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Properties of recombinant human cytosolic sialidase HsNEU2. The enzyme hydrolyzes monomerically dispersed GM1 ganglioside molecules."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M308381200"}], "href": "https://doi.org/10.1074/jbc.M308381200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14613940"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14613940"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Alessandra Mozzi, Pietro Mazzacuva, Giuseppe Zampella, et al. 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