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

Jere P. Segrest, Martin K. Jones, Andrea Catte, Medha Manchekar, Geeta Datta, Lei Zhang, Robin Zhang, Ling Li, James C. Patterson, Mayakonda N. Palgunachari, Jack F. Oram, Gang Ren

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


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 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.

Original languageEnglish (US)
Article number3193
Pages (from-to)1214-1226
Number of pages13
Issue number7
StatePublished - Jul 9 2015

Bibliographical note

Funding Information:
Thanks to UAB Information Technology and Department of Mechanical Engineering for use of the cluster Cheaha. A.C. thanks Manjula Chaddha, G.M. Anantharamaiah, and Vinod Mishra for helpful discussions. Thanks also to J.C. Gumbart of the Georgia Institute of Technology School of Physics for helpful discussions about lipid pressure profiles. Work supported by NIH grants P01HL34343 and R01HL102515 to J.P.S. Work at the Molecular Foundry was supported by the Office of Science, Office of Basic Energy Sciences, of the US Department of Energy under Contract No. DE-AC02-05CH11231 .

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