Structure, mechanism, and inhibition of Hedgehog acyltransferase
Copyright policy )Structure, mechanism, and inhibition of Hedgehog acyltransferase
The Sonic Hedgehog (SHH) morphogen pathway is fundamental for embryonic development and stem cell maintenance and is implicated in various cancers. A key step in signaling is transfer of a palmitate group to the SHH N terminus, catalyzed by the multi-pass transmembrane enzyme Hedgehog acyltransferase (HHAT). We present the high-resolution cryo-EM structure of HHAT bound to substrate analog palmityl-coenzyme A and a SHH-mimetic megabody, revealing a heme group bound to HHAT that is essential for HHAT function. A structure of HHAT bound to potent small-molecule inhibitor IMP-1575 revealed conformational changes in the active site that occlude substrate binding. Our multidisciplinary analysis provides a detailed view of the mechanism by which HHAT adapts the membrane environment to transfer an acyl chain across the endoplasmic reticulum membrane. This structure of a membrane-bound O-acyltransferase (MBOAT) superfamily member provides a blueprint for other protein-substrate MBOATs and a template for future drug discovery.
- Imperial College London United Kingdom
- Vlaams Instituut voor Biotechnologie Belgium
- VIB-VUB Center for Structural Biology Belgium
- Vrije Universiteit Brussel Belgium
- University of Oxford United Kingdom
Protein Conformation, Hedgehog acyl transferase, Acylation, Sonic Hedgehog signaling, CRYO-EM, Catalytic Domain, Chlorocebus aethiops, Enzyme Inhibitors, PALMITOYLATION, heme, 11 Medical and Health Sciences, REFINEMENT, Palmitoyl Coenzyme A, ALGORITHMS, drug, small molecule inhibitor, cryo-EM structure, COS Cells, integral membrane protein, Life Sciences & Biomedicine, Signal Transduction, 570, Biochemistry & Molecular Biology, STRUCTURE VALIDATION, PROTEINS, 610, membrane-bound O-acyltransferase, Heme, Molecular Dynamics Simulation, Article, Structure-Activity Relationship, Allosteric Regulation, Animals, Humans, Hedgehog Proteins, Science & Technology, IDENTIFICATION, Cryoelectron Microscopy, RECOGNITION, Membrane Proteins, Cell Biology, molecular dynamics simulations, 06 Biological Sciences, palmitoyl co enzyme A, HEK293 Cells, VISUALIZATION, Acyltransferases, GENERATION, Developmental Biology
Protein Conformation, Hedgehog acyl transferase, Acylation, Sonic Hedgehog signaling, CRYO-EM, Catalytic Domain, Chlorocebus aethiops, Enzyme Inhibitors, PALMITOYLATION, heme, 11 Medical and Health Sciences, REFINEMENT, Palmitoyl Coenzyme A, ALGORITHMS, drug, small molecule inhibitor, cryo-EM structure, COS Cells, integral membrane protein, Life Sciences & Biomedicine, Signal Transduction, 570, Biochemistry & Molecular Biology, STRUCTURE VALIDATION, PROTEINS, 610, membrane-bound O-acyltransferase, Heme, Molecular Dynamics Simulation, Article, Structure-Activity Relationship, Allosteric Regulation, Animals, Humans, Hedgehog Proteins, Science & Technology, IDENTIFICATION, Cryoelectron Microscopy, RECOGNITION, Membrane Proteins, Cell Biology, molecular dynamics simulations, 06 Biological Sciences, palmitoyl co enzyme A, HEK293 Cells, VISUALIZATION, Acyltransferases, GENERATION, Developmental Biology
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