Double superhelix model of high density lipoprotein.
High density lipoprotein (HDL), the carrier of so-called "good" cholesterol, serves as the major athero-protective lipoprotein and has emerged as a key therapeutic target for cardiovascular disease. We applied small angle neutron scattering (SANS) with contrast variation and selective isotopic deuteration to the study of nascent HDL to obtain the low resolution structure in solution of the overall time-averaged conformation of apolipoprotein AI (apoA-I) versus the lipid (acyl chain) core of the particle. Remarkably, apoA-I is observed to possess an open helical shape that wraps around a central ellipsoidal lipid phase. Using the low resolution SANS shapes of the protein and lipid core as scaffolding, an all-atom computational model for the protein and lipid components of nascent HDL was developed by integrating complementary structural data from hydrogen/deuterium exchange mass spectrometry and previously published constraints from multiple biophysical techniques. Both SANS data and the new computational model, the double superhelix model, suggest an unexpected structural arrangement of protein and lipids of nascent HDL, an anti-parallel double superhelix wrapped around an ellipsoidal lipid phase. The protein and lipid organization in nascent HDL envisages a potential generalized mechanism for lipoprotein biogenesis and remodeling, biological processes critical to sterol and lipid transport, organismal energy metabolism, and innate immunity.
Wu
Zhiping
Z
Department of Cell Biology, Cleveland Clinic, Cleveland, Ohio 44195; Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, Ohio 44195.
Gogonea
Valentin
V
Department of Cell Biology, Cleveland Clinic, Cleveland, Ohio 44195; Department of Chemistry, Cleveland State University, Cleveland, Ohio 44115.
Lee
Xavier
X
Department of Cell Biology, Cleveland Clinic, Cleveland, Ohio 44195; Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, Ohio 44195.
Wagner
Matthew A
MA
Department of Cell Biology, Cleveland Clinic, Cleveland, Ohio 44195; Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, Ohio 44195.
Li
Xin-Min
XM
Department of Cell Biology, Cleveland Clinic, Cleveland, Ohio 44195; Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, Ohio 44195.
Huang
Ying
Y
Department of Cell Biology, Cleveland Clinic, Cleveland, Ohio 44195; Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, Ohio 44195.
Undurti
Arundhati
A
Department of Cell Biology, Cleveland Clinic, Cleveland, Ohio 44195; Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, Ohio 44195.
May
Roland P
RP
Institut Laue-Langevin, 6 Rue Jules Horowitz, BP 156, 38042 Grenoble Cedex 9, France.
Haertlein
Michael
M
Institut Laue-Langevin, 6 Rue Jules Horowitz, BP 156, 38042 Grenoble Cedex 9, France.
Moulin
Martine
M
Institut Laue-Langevin, 6 Rue Jules Horowitz, BP 156, 38042 Grenoble Cedex 9, France.
Gutsche
Irina
I
Unit of Virus-Host Interaction, Unité Mixte de Recherche 5233 Université Joseph Fourier-European Molecular Biology Laboratory-CNRS, 6 Rue Jules Horowitz, BP 181, 38042 Grenoble Cedex 9, France.
Zaccai
Giuseppe
G
Institut Laue-Langevin, 6 Rue Jules Horowitz, BP 156, 38042 Grenoble Cedex 9, France; Institut de Biologie Structurale, Commissariat à l'Energie Atomique-CNRS-Université Joseph Fourier, 38027 Grenoble, France.
DiDonato
Joseph A
JA
Department of Cell Biology, Cleveland Clinic, Cleveland, Ohio 44195; Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, Ohio 44195.
Hazen
Stanley L
SL
Department of Cell Biology, Cleveland Clinic, Cleveland, Ohio 44195; Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, Ohio 44195; Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195. Electronic address: hazens@ccf.org.
D016632:Apolipoprotein A-I / Q000737:chemistry* / Q000378:metabolism; D001692:Biological Transport / Q000502:physiology; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology; D008055:Lipids / Q000737:chemistry*; D008075:Lipoproteins, HDL / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D020836:Protein Structure, Quaternary / Q000502:physiology; D017433:Protein Structure, Secondary / Q000502:physiology
D016632:Apolipoprotein A-I; D008055:Lipids; D008075:Lipoproteins, HDL