{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPTCH1 is the central receptor of the Hedgehog signaling pathway, acting as a key tumor suppressor and regulator of developmental processes. In its unliganded state PTCH1 inhibits the activity of Smoothened (SMO), thereby maintaining low levels of pathway‐activation; when Hedgehog ligands bind PTCH1 this inhibition is relieved, ultimately regulating cell proliferation, differentiation, and survival. In addition, PTCH1 functions as a dependence receptor that can actively trigger apoptosis in the absence of its ligand, and its structure and conserved transporter‐like features suggest that it may indirectly regulate signaling by modulating the distribution or concentration of small molecules such as cholesterol. Genetic studies have demonstrated that PTCH1 mutations underlie disorders such as Gorlin syndrome and contribute to sporadic tumors (e.g. basal cell carcinomas, medulloblastomas, keratocystic odontogenic tumors) and even influence quantitative traits like adult height and lung function. Moreover, epigenetic mechanisms and microRNAs (for example, miR‐212 and miR‐9) have been shown to regulate PTCH1 expression in various cancers, while altered promoter methylation in tumors such as breast carcinoma further confirms its pivotal role in tumorigenesis and tissue homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent structural and mechanistic studies have illuminated the molecular architecture of PTCH1. Cryo‐electron microscopy analyses reveal that PTCH1 adopts a 12‐transmembrane conformation with two extracellular domains and a sterol‐sensing domain that binds cholesterol‐like molecules in defined pockets. These high‐resolution structures show that Hedgehog ligands engage PTCH1 through multiple interfaces—including palmitoylated and calcium‐mediated contacts—and induce conformational rearrangements that allow PTCH1’s ciliary removal and the subsequent derepression of SMO. Such insights highlight a unique mechanism in which PTCH1 may function as a transporter regulating cholesterol accessibility, thereby serving as a second messenger in Hedgehog signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "28", "end_ref": "37"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Mi-Yeon Kim, Hyun Jeong Park, Seung-Cheol Baek, et al. 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