Structures of human Patched and its complex with native palmitoylated Sonic Hedgehog

By Xiaofeng Qi, P. Schmiege, E. Coutavas, Jiawei Wang, Xiaochun Li. 2018

167 citations recorded by the source corpus.

Hedgehog (HH) signalling governs embryogenesis and adult tissue homeostasis in mammals and other multicellular organisms1–3. Whereas deficient HH signalling leads to birth defects, unrestrained HH signalling is implicated in human cancers2,4–6. 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) protein7. 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-receptors8. 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. High-resolution structures of the human plasma membrane protein patched 1 alone and in complex with the native form of the ligand sonic hedgehog are determined.

Subfields: Molecular Biology

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Citations in the corpus

Structure, mechanism, and inhibition of Hedgehog acyltransferase (2021, background): “, 1995), and is only visible in the SHH-PTCH1 complex structure where the N-terminal SHH palmitate protrudes into the PTCH1 core (Qi et al., 2018; Rudolf et al., 2019).”
Two Patched molecules engage distinct sites on Hedgehog yielding a signaling-competent complex (2018, background): “not respond to HH-N (22), supporting our current observations.”
Mechanistic insights into the generation and transduction of Hedgehog Signaling (2020, background): “Although His-tagged SHH-N can bind PTCH1 with less affinity than native SHH-N, Ca2+ in the solution or medium can enhance the binding between His-tagged SHH-N and PTCH1 [55].”