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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.

Original publication

DOI

10.1016/j.molcel.2021.11.018

Type

Journal article

Journal

Mol Cell

Publication Date

16/12/2021

Volume

81

Pages

5025 - 5038.e10

Keywords

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