Structure, mechanism, and inhibition of Hedgehog acyltransferase

Journal article

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.

Authors: Coupland, CE; Andrei, SA; Ansell, TB; Carrique, L; Kumar, P

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: Molecular Cell
• Volume: 81
• Issue: 24
• Pages: 5025-5038
• Publication date: 2021-12-09
• Acceptance date: 2021-11-17
• DOI: 10.1016/j.molcel.2021.11.018
• EISSN: 1097-4164
• ISSN: 1097-2765
• Pmid: 34890564
• Language: English
• Keywords: Cryo-EM structure; Membrane-bound O-acyltransferase; Hedgehog acyl transferase; Drug; Integral membrane protein; Heme; Molecular dynamics simulations; Palmitoyl co enzyme A; Sonic Hedgehog signaling; Small molecule inhibitor