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Structure paper

タイトル	Structures of human Patched and its complex with native palmitoylated sonic hedgehog.
ジャーナル・号・ページ	Nature, Vol. 560, Issue 7716, Page 128-132, Year 2018
掲載日	2018年7月11日
著者	Xiaofeng Qi / Philip Schmiege / Elias Coutavas / Jiawei Wang / Xiaochun Li /
PubMed 要旨	Hedgehog (HH) signalling governs embryogenesis and adult tissue homeostasis in mammals and other multicellular organisms. Whereas deficient HH signalling leads to birth defects, unrestrained HH ...Hedgehog (HH) signalling governs embryogenesis and adult tissue homeostasis in mammals and other multicellular organisms. Whereas deficient HH signalling leads to birth defects, unrestrained HH signalling is implicated in human cancers. N-terminally palmitoylated HH releases the repression of Patched to the oncoprotein smoothened (SMO); however, the mechanism by which HH recognizes Patched is unclear. Here we report cryo-electron microscopy structures of human patched 1 (PTCH1) alone and in complex with the N-terminal domain of 'native' sonic hedgehog (native SHH-N has both a C-terminal cholesterol and an N-terminal fatty-acid modification), at resolutions of 3.5 Å and 3.8 Å, respectively. The structure of PTCH1 has internal two-fold pseudosymmetry in the transmembrane core, which features a sterol-sensing domain and two homologous extracellular domains, resembling the architecture of Niemann-Pick C1 (NPC1) protein. The palmitoylated N terminus of SHH-N inserts into a cavity between the extracellular domains of PTCH1 and dominates the PTCH1-SHH-N interface, which is distinct from that reported for SHH-N co-receptors. Our biochemical assays show that SHH-N may use another interface, one that is required for its co-receptor binding, to recruit PTCH1 in the absence of a covalently attached palmitate. Our work provides atomic insights into the recognition of the N-terminal domain of HH (HH-N) by PTCH1, offers a structural basis for cooperative binding of HH-N to various receptors and serves as a molecular framework for HH signalling and its malfunction in disease.
リンク	Nature / PubMed:29995851 / PubMed Central
手法	EM (単粒子)
解像度	3.5 - 3.8 Å
構造データ	7795 6oeu EMDB-7795, PDB-6oeu: Structure of human Patched1 手法: EM (単粒子) / 解像度: 3.5 Å 7796 6oev EMDB-7796, PDB-6oev: Structure of human Patched1 in complex with native Sonic Hedgehog 手法: EM (単粒子) / 解像度: 3.5 Å
化合物	ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose / N-アセチル-β-D-グルコサミン ChemComp-ZN: Unknown entry
由来	homo sapiens (ヒト)
キーワード	MEMBRANE PROTEIN / tumor suppressor / Hh