The long standing objectives of my research are to provide the detailed structural and dynamic description of the plasma lipoproteins and apolipoproteins that is crucial to understanding the molecular mechanisms of such physiological processes as lipoprotein formation, receptor interactions, lipoprotein inter-conversions, and apoprotein exchange together with the changes in these characteristics that underlie the pathophysiology of atherosclerosis. Our research has been a component of a Program Project since its inception in 1980 and I have led the Program since 2001, taking over from Dr. Small. Building on initial training in diffraction methods and biophysics, I have maintained and expanded my expertise in state-of-the-art methods of molecular biophysics and structural biology including crystallography, electron microscopy/image processing, calorimetry and thermodynamics, circular dichroism, and molecular modeling/mechanics to probe the structure-function relationships of the lipoproteins and apolipoproteins. This includes a one year sabbatical at the MRC Laboratory of Molecular Biology, Cambridge, England developing electron microscopy.
My long standing research program has involved many collaborations with current and past Program Project investigators, particularly Drs. Gursky, Small, and McKnight. Our previous work over more than three decades has focused on the structural and thermodynamic properties of specific lipoproteins (HDL and LDL), and apolipoproteins, particularly apoA-1, together with studies of the LDL receptor. We derived the first structural description of HDL, nascent HDL and LDL using x-ray methods. Our mutation studies of the conformation, stability, and lipid binding properties have contributed to providing a framework for understanding the molecular properties of apoA-1. Furthermore, our studies of peptides representing segments of apoA-1, together with “idealized” sequence models, have provided information on the role of specific residues and domains, and their interactions in the structure and stability of apoA-1. For LDL, we pioneered the use of cryo-electron microscopy to study LDL structure and used mAb labeling to investigate the topology of apoB. In collaborations with Dr. Graham Shipley, a long standing collaborator and colleague, our approach for the LDL receptor has focused on structural studies of the functional extracellular domain of the receptor reconstituted into lipid vesicles.
- Chair, Physiology & Biophysics, Boston University School of Medicine
- Research Professor, Biochemistry, Boston University School of Medicine
- Graduate Faculty (Primary Mentor of Grad Students), Boston University School of Medicine, Division of Graduate Medical Sciences
- Council for National Academic Awards, PhD
- The City University, BSc
- Published on 12/5/2017
Gorshkova IN, Mei X, Atkinson D. Arginine 123 of apolipoprotein A-I is essential for lecithin:cholesterol acyltransferase activity. J Lipid Res. 2017 Dec 05. PMID: 29208698.
- Published on 11/13/2017
Melchior JT, Walker RG, Cooke AL, Morris J, Castleberry M, Thompson TB, Jones MK, Song HD, Rye KA, Oda MN, Sorci-Thomas MG, Thomas MJ, Heinecke JW, Mei X, Atkinson D, Segrest JP, Lund-Katz S, Phillips MC, Davidson WS. A consensus model of human apolipoprotein A-I in its monomeric and lipid-free state. Nat Struct Mol Biol. 2017 Dec; 24(12):1093-1099. PMID: 29131142.
- Published on 2/13/2017
Gorshkova IN, Atkinson D. Increased Binding of Apolipoproteins A-I and E4 to Triglyceride-Rich Lipoproteins is linked to Induction of Hypertriglyceridemia. JSM Atheroscler. 2017; 2(2). PMID: 28597004.
- Published on 6/17/2016
Mei X, Liu M, Herscovitz H, Atkinson D. Probing the C-terminal domain of lipid-free apoA-I demonstrates the vital role of the H10B sequence repeat in HDL formation. J Lipid Res. 2016 Aug; 57(8):1507-17. PMID: 27317763.
- Published on 6/3/2015
Mei X, Atkinson D. Lipid-free Apolipoprotein A-I Structure: Insights into HDL Formation and Atherosclerosis Development. Arch Med Res. 2015 Jul; 46(5):351-60. PMID: 26048453.
- Published on 6/11/2014
Gorshkova IN, Mei X, Atkinson D. Binding of human apoA-I[K107del] variant to TG-rich particles: implications for mechanisms underlying hypertriglyceridemia. J Lipid Res. 2014 Sep; 55(9):1876-85. PMID: 24919401.
- Published on 4/28/2014
Das M, Mei X, Jayaraman S, Atkinson D, Gursky O. Amyloidogenic mutations in human apolipoprotein A-I are not necessarily destabilizing - a common mechanism of apolipoprotein A-I misfolding in familial amyloidosis and atherosclerosis. FEBS J. 2014 Jun; 281(11):2525-42. PMID: 24702826.
- Published on 12/5/2013
Wang L, Mei X, Atkinson D, Small DM. Surface behavior of apolipoprotein A-I and its deletion mutants at model lipoprotein interfaces. J Lipid Res. 2014 Mar; 55(3):478-92. PMID: 24308948.
- Published on 9/13/2013
Gursky O, Jones MK, Mei X, Segrest JP, Atkinson D. Structural basis for distinct functions of the naturally occurring Cys mutants of human apolipoprotein A-I. J Lipid Res. 2013 Dec; 54(12):3244-57. PMID: 24038317.
- Published on 12/28/2012
Khachfe HM, Atkinson D. Conformation and stability properties of B17: II. Analytical investigations using differential scanning calorimetry. Eur Biophys J. 2013 Apr; 42(4):309-14. PMID: 23271513.
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