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Jere Segrest, MD, PhD
Gerontology & Geriatric Medicine, School of Medicine
BDB 630 Zip 0012
Jere P. Segrest (b. 1940) obtained his B.A., M.D. and Ph.D. (Biochemistry) at Vanderbilt University. Postdoctoral studies at NIH resulted in elucidation of the hydrophobic a helical transmembrane domain of glycophorin, the first transmembrane protein so characterized, and development of the theory of the arnphipathic a helix. In recent years his lab developed the first detailed molecular models for HDL and for the assembly of apo B-containing lipoproteins and is currently working on a detailed molecular model for LDL. His team approaches these research topics through use of computer-based molecular modeling and dynamics, rational design and synthesis of peptide analogs, and over-expression of rationally designed site-directed mutant human apolipoproteins in cells in culture and in transgenic mouse models. He is presently the Director of the Atherosclerosis Research Unit and the Atherosclerois Reversal and Lipid Clinic. Outside interests include reading classical Greek and Roman history and science fiction and bicycling.
Structural Biology of Supramolecular Assemblies (Particularly Lipoproteins and Membranes)
Dr. Segrest is a Professor of Medicine, Biochemistry and Molecular Genetics and Pathology, Director of the Atherosclerosis Research Unit and Director of the Atherosclerosis Reversal and Lipid Clinic. He is the Program Director for an NHLBI Program Project, P01HL34343, “Amphipathic Motifs, Lipoproteins And Atherosclerosis” that focuses on development of a comprehensive theory of the interaction of amphipathic motifs with lipid to: (a) determine the minimal structural features of apoA-I that can prevent and/or reverse atherosclerosis, (b) determine the minimal structural features of apoB that are involved in both the biosynthesis of apoB-containing lipoproteins and the structure, function and properties of LDL, and (c) apply this knowledge to understand mechanisms involved in prevention and reversal of atherosclerosis and potentially for the development of pharmacological agents. Proteins that insert into membrane lipids are fundamental to biology and medicine. Dr. Segrest’s research goals have been guided by a recognition that lipid-water interfaces leave a signature in those proteins evolutionarily adapted to interact with lipids. Two "lipid signatures" have been discovered by his research program, the amphipathic ? helix (1) and the amphipathic ? sheet (2). These two "lipid signatures" are being used in three separate studies of the structural biology of plasma lipoproteins. i)He developed the first detailed molecular model for HDL and is currently testing the model by site-directed mutagenesis and molecular dynamics simulations. ii) He developed a molecular model for the assembly of apoB-containing particles and is currently testing the model by site-directed mutagenesis and molecular modeling. iii) Finally, he is in the process of developing a detailed molecular model for LDL. His team approaches these research topics through use of computer-based molecular modeling and dynamics, rational design and synthesis of peptide analogs, and over-expression of rationally designed site-directed mutant human apolipoproteins in E. coli, in mammalian cells in culture, and in transgenic mouse models of atherosclerosis.
- Dashti, N., Gandhi, M., Liu, X., Lin, X., and Segrest, J. P. (2002). The N-terminal 1000 residues of apolipoprotein B associate with microsomal triglyceride transfer protein to create a lipid transfer pocket required for lipoprotein assembly. Biochemistry 41, 6978-87. 12033930
- Segrest, J. P., Jones, M. K., De Loof, H., and Dashti, N. (2001). Structure of apolipoprotein B-100 in low density lipoproteins. J Lipid Res 42, 1346-67. 11518754
- Garber, D. W., Datta, G., Chaddha, M., Palgunachari, M. N., Hama, S. Y., Navab, M., Fogelman, A. M., Segrest, J. P., and Anantharamaiah, G. M. (2001). A new synthetic class A amphipathic peptide analogue protects mice from diet-induced atherosclerosis. J Lipid Res 42, 545-552. 11290826
- Segrest, J. P., Li, L., Anantharamaiah, G. M., Harvey, S. C., Liadaki, K. N., and Zannis, V. (2000). Structure and function of apolipoprotein A-I and high-density lipoprotein. Curr Opin Lipidol 11, 105-15. 10787171
- Segrest, J. P., Jones, M. K., Klon, A. E., Sheldahl, C. J., Hellinger, M., De Loof, H., and Harvey, S. C. (1999). A detailed molecular belt model for apolipoprotein A-I in discoidal high density lipoprotein. J Biol Chem 274, 31755-8. 10542194
- Segrest, J. P., Jones, M. K., and Dashti, N. (1999). N-terminal domain of apolipoprotein B has structural homology to lipovitellin and microsomal triglyceride transfer protein: a "lipid pocket" model for self-assembly of apob-containing lipoprotein particles. J Lipid Res 40, 1401-16. 10428976
- Hristova, K., Wimley, W. C., Mishra, V. K., Anantharamiah, G. M., Segrest, J. P., and White, S. H. (1999). An amphipathic alpha-helix at a membrane interface: a structural study using a novel X-ray diffraction method. J Mol Biol 290, 99-117. 10388560
- Segrest, J. P., Jones, M. K., Mishra, V. K., and Anantharamaiah, G. M. (2002). Experimental and computational studies of the interactions of amphipathic peptides with lipid surfaces. Current Topics in Membranes 52, 391-429.