Structural insights into MBOAT2 catalysis, product retention, and ligand exchange
MBOAT2 suppresses ferroptosis independently of GPX4 and FSP1 by transferring monounsaturated acyl chains from acyl-CoA donors to lysophospholipid acceptors, but the structural basis of its catalytic cycle remains unclear. Here, we report the first cryo-EM structures of human MBOAT2, capturing endogenous and substrate-induced ligand-bound states. Unexpectedly, as-purified MBOAT2 contains a…
MBOAT2 is a protein that prevents ferroptosis without relying on GPX4 or FSP1. It achieves this by transferring monounsaturated acyl chains from acyl-CoA donors to lysophospholipid acceptors. However, the precise mechanism behind its catalytic process has remained enigmatic.
To unravel this mystery, researchers have now obtained the first cryo-EM structures of human MBOAT2. These structures showcase both endogenous and substrate-induced ligand-bound states. Surprisingly, the purified MBOAT2 protein shows a phospholipid-like density associated with a retained product, alongside another density at a potential acyl-donor entry site.
When Oleoyl-CoA is added, the ordered product-like density decreases, and donor density becomes apparent. Conversely, when LPE (lysophospholipid equivalent) is introduced, local heterogeneity near the archway intensifies. Notably, the inactive H373A mutant exhibits endogenous donor- and acceptor-like densities along the two access pathways, suggesting substrate preloading.
These newly acquired structures elucidate the catalytic machinery of MBOAT2, substantiate the idea of product retention with a donor-primed working model, and offer templates for the guided development of potential ligands.
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