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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 acyltransferas...

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Published in:Molecular cell 2021-12, Vol.81 (24), p.5025-5038.e10
Main Authors: Coupland, Claire E., Andrei, Sebastian A., Ansell, T. Bertie, Carrique, Loic, Kumar, Pramod, Sefer, Lea, Schwab, Rebekka A., Byrne, Eamon F.X., Pardon, Els, Steyaert, Jan, Magee, Anthony I., Lanyon-Hogg, Thomas, Sansom, Mark S.P., Tate, Edward W., Siebold, Christian
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Language:English
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Summary: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. [Display omitted] •High-resolution cryo-EM structure of HHAT in complex with a SHH-mimetic megabody•Heme is bound to HHAT Cys324 in a membrane cavity and is essential for function•Palm-CoA binds in a central HHAT cavity adjacent to the catalytic histidine•The competitive inhibitor IMP-1575 causes conformational changes in the active site HHAT is a key enzyme in the Hedgehog signaling pathway and protein-substrate member of the membrane-bound O-acyltransferase (MBOAT) superfamily. Coupland et al. report the cryo-EM structures of HHAT bound to acyl-donor substrate, megabody, and inhibitor IMP-1575, providing insight into the structure-function relationship of HHAT, mechanism, and the basis for inhibition.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2021.11.018