Document Type

Article

Publication Date

4-1-2013

Publication Title

Journal of Lipid Research

Abstract

High density lipoproteins (HDL) are athero-protective particles under investigation as potential therapeutic agents for cardiovascular disease. We applied small angle neutron scattering (SANS) with contrast variation to obtain the low resolution structure of nascent HDL (nHDL) reconstituted with dimyristoyl phosphatidyl choline (DMPC), apoA1:DMPC (1:80, mol:mol). The overall shape of the entire particle is discoidal, with low resolution architecture of apoA1 visualized as an open, contorted, and slightly out of plane structure with three arms, while the low resolution shape of the lipid phase is an oblate ellipsoid that fits well within the protein shape. Modeling studies incorporating the SANS data indicate that apoA1 within the lipoprotein is folded onto itself, making a hairpin, which was also confirmed independently by both cross-linking mass spectrometry and hydrogen-deuterium exchange mass spectrometry analyses. The open conformation of apoA1 observed coupled with the lipid shape indicate that the lipid is predominantly a bilayer with a small micelle domain between the open apoA1 arms. Collectively, these studies demonstrate that full length apoA1 retains an open architecture that is dictated by its lipid cargo. This configuration may help accommodate potential changing lipid cargo content of the particle by quantized expansion of hairpin structures in apoA1

Comments

This study was supported by National Institutes of Health Grants P01 HL-098055, P01 HL-076491, and by the Leduc Foundation.

DOI

10.1194/jlr.M032763

Version

Publisher's PDF

Volume

54

Issue

4

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