{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNPC2 is a small, soluble lysosomal protein that binds cholesterol with high affinity and plays an essential role in the egress of lipoprotein‐derived cholesterol from late endosomal/lysosomal compartments. Biochemical and biophysical studies have demonstrated that NPC2 directly interacts with membranes—its cholesterol‐bound form engaging in a “hydrophobic handoff” with the amino‐terminal domain of NPC1—and that this process is facilitated by specific lipid microenvironment factors such as lysobisphosphatidic acid (LBPA). Structural analyses and mutagenesis experiments have delineated key surface patches and cholesterol binding pockets that underpin its rapid, collisional transfer mechanism, as well as the dynamic repositioning required for effective cholesterol uptake from and delivery to membranes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMutational studies and clinical investigations have underscored that precise NPC2 structure is critical for its function in intracellular cholesterol trafficking. A spectrum of naturally occurring missense and truncating mutations has been characterized, with several studies showing that alterations in key residues or disruptions in posttranslational processing (e.g., glycosylation) lead to loss of cholesterol‐binding capacity, misfolding, or improper trafficking—all of which are associated with the clinical phenotype of Niemann–Pick disease type C. Furthermore, interactions with other proteins such as the Nogo‐B receptor (NgBR) and glycine N‐methyltransferase (GNMT) have been shown to enhance NPC2 stability and function, while deficits in NPC2 activity also impair the generation of cholesterol‐derived oxysterols that are important for cellular sterol regulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical role in lysosomal cholesterol export, NPC2 has been implicated in extra‐lysosomal processes that influence overall cellular cholesterol homeostasis. In several cellular models, NPC2 contributes to mitochondrial cholesterol delivery, thereby impacting steroidogenesis and mitochondrial quality control, and it is vital for proper mitophagy and regulation of inflammatory signaling in adipocytes. Moreover, NPC2 influences host defense mechanisms—its expression being necessary for vitamin A–induced cholesterol reduction in monocytes—and its altered expression has been observed in the liver, reproductive tissues, and even in hepatocellular carcinoma, while genetic variants may also modify Alzheimer’s disease risk. Collectively, these findings reveal that NPC2 not only governs intracellular cholesterol trafficking through direct interactions with membranes and partner proteins but also plays a broader role in maintaining cholesterol balance across diverse tissues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Michael L Wang, Massoud Motamed, Rodney E Infante, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "The integrity of a cholesterol-binding pocket in Niemann-Pick C2 protein is necessary to control lysosome cholesterol levels."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0530027100"}], "href": "https://doi.org/10.1073/pnas.0530027100"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12591949"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12591949"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Sunita R Cheruku, Zhi Xu, Roxanne Dutia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mechanism of cholesterol transfer from the Niemann-Pick type C2 protein to model membranes supports a role in lysosomal cholesterol transport."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M602765200"}], "href": "https://doi.org/10.1074/jbc.M602765200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16606609"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16606609"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Xiaochun Li, Piyali Saha, Jian Li, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Intracellular cholesterol trafficking is dependent upon NPC2 interaction with lysobisphosphatidic acid."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.50832"}], "href": "https://doi.org/10.7554/eLife.50832"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31580258"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31580258"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Giray Enkavi, Heikki Mikkolainen, Burçin Güngör, et al. 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