The objective of this program is to understand the Structural Biology of the macromolecular complexes involved in the transport of lipids into and out of cells.
The aims of the project are: to define the 3-dimensional structures of cellular receptors and their ligands bound to LDL (Project 1): to study the formation of primordial nascent triglyceride-rich particles in the endoplasmic reticulum and understand how the secondary and tertiary structures of the N-terminal 41% apo-B regulates this process (Project 2); to understand the structure and conformation of apo-B, the 3- dimensional structure of LDL, the organization of apo-B on LDL, and to define the formation and 3-dimensional structure of exchangeable apolipoproteins on nascent ans plasma HDL (Project 3); to understand the binding of fatty acids to albumin, the transfer of fatty acids from albumin and movement across membranes into cells, structural and dynamic features of intracellular fatty acid binding proteins, and the effect of fatty acids on intracellular Ph (Project 4). State-of-the-art techniques of structural biology are used to study isolated or reconstituted macromolecular complexes. Low resolution structures of individual particles (and/or 2 dimensional arrays) often decorated with site specific labels are obtained by electron microscopy, in particular cryo-EM, combined with image analysis and reconstruction. Detailed structures of individual proteins or protein-lipid complexes are determined by x-ray crystallography. The solution structure of peptides that model regions of proteins or small proteins such as the intracellular fatty acid binding proteins are determined by multi-dimensional NMR. High resolution molecular arrangements can be superimposed onto the low resolution structure of macromolecular assemblies obtained by electron microscopy to generate a """"""""higher resolution"""""""" macromolecular structure. These studies can provide the biological structures involved in the processes by which lipids are moved into, within, and out of cells. Such information will allow the development of new molecular based strategies to control hyper beta lipoproteinemia, fatty acid-induced cellular damage in ischemia, and arteriosclerosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Srinivas, Pothur R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Boston University
Schools of Medicine
United States
Zip Code
Melchior, John T; Walker, Ryan G; Cooke, Allison L et al. (2017) A consensus model of human apolipoprotein A-I in its monomeric and lipid-free state. Nat Struct Mol Biol 24:1093-1099
Gursky, Olga (2015) Structural stability and functional remodeling of high-density lipoproteins. FEBS Lett 589:2627-39
Mei, Xiaohu; Atkinson, David (2015) Lipid-free Apolipoprotein A-I Structure: Insights into HDL Formation and Atherosclerosis Development. Arch Med Res 46:351-60
Wang, Libo; Mei, Xiaohu; Atkinson, David et al. (2014) Surface behavior of apolipoprotein A-I and its deletion mutants at model lipoprotein interfaces. J Lipid Res 55:478-92
Gorshkova, Irina N; Mei, Xiaohu; Atkinson, David (2014) Binding of human apoA-I[K107del] variant to TG-rich particles: implications for mechanisms underlying hypertriglyceridemia. J Lipid Res 55:1876-85
Mitsche, Matthew A; Packer, Laura E; Brown, Jeffrey W et al. (2014) Surface tensiometry of apolipoprotein B domains at lipid interfaces suggests a new model for the initial steps in triglyceride-rich lipoprotein assembly. J Biol Chem 289:9000-12
Mitsche, Matthew A; Small, Donald M (2013) Surface pressure-dependent conformation change of apolipoprotein-derived amphipathic ?-helices. J Lipid Res 54:1578-88
Gursky, Olga (2013) Crystal structure of ?(185-243)ApoA-I suggests a mechanistic framework for the protein adaptation to the changing lipid load in good cholesterol: from flatland to sphereland via double belt, belt buckle, double hairpin and trefoil/tetrafoil. J Mol Biol 425:1-16
Khachfe, Hassan M; Atkinson, David (2013) Conformation and stability properties of B17: II. Analytical investigations using differential scanning calorimetry. Eur Biophys J 42:309-14
Meyers, Nathan L; Wang, Libo; Small, Donald M (2012) Apolipoprotein C-I binds more strongly to phospholipid/triolein/water than triolein/water interfaces: a possible model for inhibiting cholesterol ester transfer protein activity and triacylglycerol-rich lipoprotein uptake. Biochemistry 51:1238-48

Showing the most recent 10 out of 235 publications