Unraveling the Molecular Mechanisms of ABHD5 Membrane Targeting

ABHD5 uses a sequential dual-site recognition of lipid droplet and endoplasmic reticulum membranes, with an N-terminal anchor and a lid-helix contact driving a conformational switch.

• Why it matters: The molecular basis of how ABHD5 recognizes membranes and regulates PNPLA2/ATGL activity is poorly understood, limiting mechanistic insight into lipid remodeling in metabolic tissues.
• What they did: The study combined multiscale molecular dynamics, hydrogen-deuterium exchange mass spectrometry, and site-directed mutagenesis to test how ABHD5 engages LD and endoplasmic reticulum membranes.
• The result: Membrane binding triggers a lid conformational switch that expands the pseudosubstrate pocket, stabilizes an open ABHD5 conformation, and couples to membrane remodeling that forms a triacylglycerol-enriched nanodomain beneath the pocket.

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