Aberrant Hedgehog (HH) signaling leads to various types of cancer and birth defects. N-terminally palmitoylated HH initiates signaling by binding its receptor Patched-1 (PTCH1). A recent 1:1 PTCH1-HH complex structure visualized a palmitate-mediated binding site on HH, which was inconsistent with previous studies that implied a distinct, calcium-mediated binding site for PTCH1 and HH co-receptors. Our 3.5-angstrom resolution cryo-electron microscopy structure of native Sonic Hedgehog (SHH-N) in complex with PTCH1 at a physiological calcium concentration reconciles these disparate findings and demonstrates that one SHH-N molecule engages both epitopes to bind two PTCH1 receptors in an asymmetric manner. Functional assays using PTCH1 or SHH-N mutants that disrupt the individual interfaces illustrate that simultaneous engagement of both interfaces is required for efficient signaling in cells.
Two critical periods of Sonic Hedgehog signaling required for the specification of motor neuron identity
Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion
Hedgehog movement is regulated through tout velu-dependent synthesis of a heparan sulfate proteoglycan
Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened
Sightless has homology to transmembrane acyltransferases and is required to generate active Hedgehog protein
Feedback control of mammalian Hedgehog signaling by the Hedgehog-binding protein, Hip1, modulates Fgf signaling during branching morphogenesis of the lung
Palmitoylation is required for the production of a soluble multimeric Hedgehog protein complex and long-range signaling in vertebrates
A highly conserved amino-terminal region of sonic hedgehog is required for the formation of its freely diffusible multimeric form
The Hedgehog-binding proteins Gas1 and Cdo cooperate to positively regulate Shh signaling during mouse development
The structure of SHH in complex with HHIP reveals a recognition role for the Shh pseudo active site in signaling.
Structural insights into hedgehog ligand sequestration by the human hedgehog-interacting protein HHIP.
Overlapping roles and collective requirement for the coreceptors GAS1, CDO, and BOC in SHH pathway function.
Boc and Gas1 each form distinct Shh receptor complexes with Ptch1 and are required for Shh-mediated cell proliferation.
Electron counting and beam-induced motion correction enable near-atomic-resolution single-particle cryo-EM
Tools for macromolecular model building and refinement into electron cryo-microscopy reconstructions
Identification of NPC1 as the target of U18666A, an inhibitor of lysosomal cholesterol export and Ebola infection
Analysis of the transcriptome data in Litopenaeus vannamei reveals the immune basis and predicts the hub regulation-genes in response to high-pH stress
Structure of Sonic Hedgehog protein in complex with zinc(II) and magnesium(II) reveals ion-coordination plasticity relevant to peptide drug design
Gli promotes tumor progression through regulating epithelial-mesenchymal transition in non-small-cell lung cancer
Quantitating the epigenetic transformation contributing to cholesterol homeostasis using Gaussian process
PKAc-directed interaction and phosphorylation of Ptc is required for Hh signaling inhibition in Drosophila
Cholesterol Transport in Wild-Type NPC1 and P691S: Molecular Dynamics Simulations Reveal Changes in Dynamical Behavior.
Molecular insights into the Patched1 drug efflux inhibitory activity of panicein A hydroquinone: a computational study.
Hedgehog pathway activation through nanobody-mediated conformational blockade of the Patched sterol conduit.
Next Generation Techniques for Determination of Protein-Protein Interactions: Beyond the Crystal Structure
Pathological Features of Tumors of the Nervous System in Hereditary Cancer Predisposition Syndromes: A Review.
Distinct Cation Gradients Power Cholesterol Transport at Different Key Points in the Hedgehog Signaling Pathway.
Distinctive functioning of STARD1 in the fetal Leydig cells compared to adult Leydig and adrenal cells. Impact of Hedgehog signaling via the primary cilium.
Cryo-EM study of patched in lipid nanodisc suggests a structural basis for its clustering in caveolae.
Identification of rare PTCH1 nonsense variant causing orofacial cleft in a Chinese family and an up-to-date genotype-phenotype analysis.
Calcium & Bioenergetics
Bioenergetic processes, including cellular respiration and photosynthesis, concern the transformation of energy by cells. Here is the latest research on the role of calcium in bioenergetics.
Birth defects encompass structural and functional alterations that occur during embryonic or fetal development and are present since birth. The cause may be genetic, environmental or unknown and can result in physical and/or mental impairment. Here is the latest research on birth defects.