Structure, mechanism, and inhibition of Hedgehog acyltransferase
File(s)
Author(s)
Type
Journal Article
Abstract
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.
Date Issued
2021-12-16
Online Publication Date
2022-03-02T12:23:40Z
Date Acceptance
2021-11-17
ISSN
1097-2765
Publisher
Cell Press
Start Page
5025
End Page
+
Journal / Book Title
Molecular Cell
Volume
81
Issue
24
Copyright Statement
Crown Copyright © 2021 Published by Elsevier Inc.
License URI
Sponsor
Cancer Research UK
Biotechnology and Biological Sciences Research Council (BBSRC)
Identifier
https://www.cell.com/molecular-cell/fulltext/S1097-2765(21)00998-9?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1097276521009989%3Fshowall%3Dtrue
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000733707000009&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
21451
BB/T01508X/1
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
STRUCTURE VALIDATION
CRYO-EM
PALMITOYLATION
IDENTIFICATION
PROTEINS
VISUALIZATION
RECOGNITION
ALGORITHMS
GENERATION
REFINEMENT
Hedgehog acyl transferase
Sonic Hedgehog signaling
cryo-EM structure
drug
heme
integral membrane protein
membrane-bound O-acyltransferase
molecular dynamics simulations
palmitoyl co enzyme A
small molecule inhibitor
Acylation
Acyltransferases
Allosteric Regulation
Animals
COS Cells
Catalytic Domain
Chlorocebus aethiops
Cryoelectron Microscopy
Enzyme Inhibitors
HEK293 Cells
Hedgehog Proteins
Heme
Humans
Membrane Proteins
Molecular Dynamics Simulation
Palmitoyl Coenzyme A
Protein Conformation
Signal Transduction
Structure-Activity Relationship
COS Cells
Animals
Humans
Heme
Palmitoyl Coenzyme A
Acyltransferases
Membrane Proteins
Enzyme Inhibitors
Cryoelectron Microscopy
Signal Transduction
Allosteric Regulation
Catalytic Domain
Protein Conformation
Structure-Activity Relationship
Acylation
Hedgehog Proteins
Molecular Dynamics Simulation
HEK293 Cells
Chlorocebus aethiops
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
STRUCTURE VALIDATION
CRYO-EM
PALMITOYLATION
IDENTIFICATION
PROTEINS
VISUALIZATION
RECOGNITION
ALGORITHMS
GENERATION
REFINEMENT
Developmental Biology
06 Biological Sciences
11 Medical and Health Sciences
Publication Status
Published