title: Surface Density-Induced Pleating of a Lipid Monolayer Drives Nascent High-Density Lipoprotein Assembly.
abstract: 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 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.
authors.affiliation: Department of Medicine and Atherosclerosis Research Unit, University of Alabama at Birmingham, Birmingham, AL 35294-0012, USA; Center for Computational and Structural Dynamics, 630 BDB, UAB, Birmingham, AL 35294, USA. Electronic address: segrest@uab.edu.
authors.forename: Jere P
authors.initials: JP
authors.lastname: Segrest
authors.affiliation: Department of Medicine and Atherosclerosis Research Unit, University of Alabama at Birmingham, Birmingham, AL 35294-0012, USA; Center for Computational and Structural Dynamics, 630 BDB, UAB, Birmingham, AL 35294, USA.
authors.forename: Martin K
authors.initials: MK
authors.lastname: Jones
authors.affiliation: Department of Medicine and Atherosclerosis Research Unit, University of Alabama at Birmingham, Birmingham, AL 35294-0012, USA; Center for Computational and Structural Dynamics, 630 BDB, UAB, Birmingham, AL 35294, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Catte
authors.affiliation: Department of Medicine and Atherosclerosis Research Unit, University of Alabama at Birmingham, Birmingham, AL 35294-0012, USA.
authors.forename: Medha
authors.initials: M
authors.lastname: Manchekar
authors.affiliation: Department of Medicine and Atherosclerosis Research Unit, University of Alabama at Birmingham, Birmingham, AL 35294-0012, USA.
authors.forename: Geeta
authors.initials: G
authors.lastname: Datta
authors.affiliation: Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Medicine and Atherosclerosis Research Unit, University of Alabama at Birmingham, Birmingham, AL 35294-0012, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35294-0012, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Patterson
authors.affiliation: Department of Medicine and Atherosclerosis Research Unit, University of Alabama at Birmingham, Birmingham, AL 35294-0012, USA.
authors.forename: Mayakonda N
authors.initials: MN
authors.lastname: Palgunachari
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA 98109, USA.
authors.forename: Jack F
authors.initials: JF
authors.lastname: Oram
authors.affiliation: Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Ren
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000737:chemistry; D021961:Cell Membrane Structures / Q000737:chemistry; D002784:Cholesterol / Q000737:chemistry; D008051:Lipid Bilayers / Q000737:chemistry*; D008075:Lipoproteins, HDL / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D010713:Phosphatidylcholines / Q000737:chemistry*
chemical_list: D064286:ATP Binding Cassette Transporter 1; D008051:Lipid Bilayers; D008075:Lipoproteins, HDL; D010713:Phosphatidylcholines; D002784:Cholesterol; C028694:1-palmitoyl-2-oleoylphosphatidylcholine