Surface Density-Induced Pleating of a Lipid Monolayer Drives Nascent High-Density Lipoprotein Assembly

Abstract

Summary Biogenesis of high density lipoproteins (HDL) is coupled to the transmembrane protein, ATP-binding cassette transporter A1 (ABCA1), which transports phospholipid (PL) from the inner to the outer membrane monolayer. Using a combination of computational and experimental approaches, we show that increased outer lipid monolayer surface density driven by excess PL or by membrane insertion of amphipathic helices, results in pleating of the outer monolayer to form membrane-attached discoidal bilayers. Apolipoprotein (apo)A-I accelerates and stabilizes the pleats. In the absence of apoA-I, pleats collapse to form vesicles. These results mimic cells overexpressing ABCA1 that, in the absence of apoA-I, form and release vesicles. We conclude that the basic driving force for nascent discoidal HDL assembly is a PL pump-induced surface density increase that produces lipid monolayer pleating. We then argue that ABCA1 forms an extracellular reservoir containing an isolated pressurized lipid monolayer decoupled from the transbilayer density buffering of cholesterol.

An Evaluation of the Crystal Structure of C-terminal Truncated Apolipoprotein A-I in Solution Reveals Structural Dynamics Related to Lipid Binding

“…Indeed, additives like isopropanol can induce a lipid-boundlike structure to otherwise lipid-free apoA-I (42). Crystal packing and other factors could also be responsible (43).…”

ABCA1-dependent sterol release: sterol molecule specificity and potential membrane domain for HDL biogenesis

“…Direct interaction between apoA-I and ABCA1 has been shown (30)(31)(32). It has also been reported that ABCA1 at the PM produces membrane deformation sites where apoA-I interacts and solubilizes lipids present in these domains to generate nascent HDL ( 33,34 ). These results lead one to speculate that the lipid compositions of nascent HDL may refl ect those of a membrane domain where nascent HDL is assembled.…”

“…The unique structural properties of lanosterol may thus allow it to be more mobile at the PM for ABCA1-dependent release. It was shown that ABCA1 creates a specifi c lipid-packing deformation site at the PM, and apoA-I recognizes and solubilizes such membrane domains to generate HDL ( 33,34 ). HDL particles generated by ABCA1 are cholesterol-rich and have similar lipid composition to lipid rafts ( 53 ), suggesting that the ABCA1/ apoA-I system generates HDL at a membrane domain containing signifi cant amounts of cholesterol.…”

Is ABCA1 a lipid transfer protein?

“…Most of the apoA-I binds with high affinity to lipid sites in the PM created by the PL translocase activity of the transporter. These lipid domains in the PM to which apoA-I binds protrude into the extracellular space (105)(106)(107) and are thought to be the sites of HDL particle assembly. It has been suggested that apoA-I must interact with ABCA1 before it can interact with PL in the PM (108).…”