Donald M. Small, M.D.
Professor of Physiology and Biophysics,
Biochemistry and Medicine
A.B. Occidental College
M.A. (Animal Physiology) Oxford University (England)
M.D. University of California, Los Angeles.
Lipoproteins and Disease
Our interests cover the general area of the physical properties of fats and oils, detergents, lipids, proteins and lipid-protein interactions. Specific systems of interest include artificial membranes (bilayers), surfaces and cores of native lipoproteins, and recombinant lipoproteins using specific lipids and either native or genetically engineered apolipoproteins. A biophysical approach is used to probe disease processes such as athersclerosis, lipoproteinemias and gallstone formation. Recent work includes: (1) physical characterization of stereospecific lipids and fats, (2) the recombination of lipids with native or genetically engineered fragments of apolipoproteins to produce recombinant lipoproteins, (3) physical analysis of recombinant lipoprotein particles and (4) studies of the metabolism of recombinant lipoproteins in whole animals, perfused livers and cell cultures. The mechanisms of progression and regression of atherosclerosis are also being pursued. A wide variety of biophysical, biochemical and physiological methods are used to probe these problems.
Dr. Small founded of the Department of Biophysics at Boston University School of Medicine and served as its Chair form 1988 to 2000. After the merger with the Department of Physiology in 2000, he served as Chair of Physiology and Biophysics until 2006 when he passed the Chair to Dr. David Atkinson. In 1980 he initiated this Program Project (HL026335) and was Program Director from 1980 to 2001. He has been the Director of Project 2 since its inception. Thus he has a long experience with the Program Project, its changes and advances throughout the past 30 years. Dr. Small, after completing a residency in internal medicine, was trained as a physical chemist with expertise in the study of bulk and surface properties of lipids. Between 1966 and 1978, he studied the physical chemistry of bile lipids. He defined the solubility of cholesterol in phospholipid/bile salt micelles (1), and related it to human bile composition and gallstone formation (2). This ignited a whole field of gallstone research which culminated in translation to drug therapy in patients to dissolve and prevent stones. His interest turned to atherosclerosis and in 1974 published a seminal paper in Science on the physical-chemical basis of lipid deposition in atherosclerosis (3). In 1986 he was selected by the AHA to give the Duff Lecture on his extensive work on the physical-biochemistry of atherosclerotic lesions. Lipoproteins and their apolipoproteins also became a target of his research and along with colleagues he discovered the order/disorder phase transition in cholesterol esters in LDL (4), the irreversible denaturation transition of apo-B on LDL (4), and unfolding transitions in apo-A1, both as a free protein and on lipid particles (5). Over 40 years he and his colleagues have studied the physical biochemistry of lipoproteins, and throughout this period he also published over 50 studies on the physical behavior of a variety of lipids. In 1986 he published, “The Physical Chemistry of Lipids, From Alkanes to Phospholipids”, a highly acclaimed 672 page source book.
By 1990 he began to explore how the primary sequence of apo-B related to its structure and how this drove the assembly with lipids to form nascent VLDL as apoB translocated across the ER. Project 2 was initiated first to study the lipoproteins secreted from cells transfected with C-terminal truncations of apo-B. In 1994, Robert Nolte (a student of Dr. Atkinson) and Dr. Jere Segrest independently showed that apoB100 and an α/β-β1-α1-β2-α2 secondary structure. In 1997, Drs. Small and Atkinson presented a more detailed model for the β1 domain of apoB (apoB21-41) as an amphipathic beta sheet 50-60Å wide and 200Å long which could recruit triglycerides into nascent lipoproteins. He then showed that this b region was responsible for recruiting triacylglycerol to the nascent particle during its translocation across the ER in cells. Since apolipoproteins are interfacial molecules, he pioneered a method to study the binding and surface properties of peptides and apolipoproteins to a drop of core lipid, e.g. triaclyglycerol. He showed that surface behavior of apolipoproteins were very different from the usual globular peptides which denature at surfaces. Amphipathic alpha helical peptides such as HDL apolipoproteins (apo-A1, apo-C1, etc.) bound TAG but could be pushed off into the aqueous phase at a specific pressure without being denatured. In contrast, amphipathic beta strands and native parts of the β1 sheet region from apo-B bound irreversibly and had pure elastic properties and thus provided an anchor for apo-B at the nascent VLDL surface. Recently using an innovative combination of Langmuir balance and tensiometer studies and application of the Gibbs 2D phase rule, he was able to coat the surface with phosphatidylcholine (PC) to produce a more native lipoprotein-like surface. Here the concentration or surface density of PC and TAG is known and can be varied as a function of pressure. Ongoing studies of various apoproteins and peptides at PC-TO/W interfaces provide a unique opportunity of studying their absorption, potential for desorption, elasticity and other properties at a more physiologic interface.
Small, D.M. 1986. The Physical Chemistry of Lipids from Alkanes to Phospholipids, Handbook of Lipid Research Series, Vol. 4, ed. D. Hanahan, Plenum Press, N.Y. pp. 1-672. (second printing 1988).
Selected Peer Reviewed Articles:
1) Small, D.M., M. Bourges, D.G. Dervichian. 1966. Ternary and quaternary aqueous system containing bile salts, lecithin and cholesterol. Nature 211:816-818.
2) Admirand, W.H., D.M. Small. 1968. The physico-chemical basis of cholesterol gallstone formation in man. J. Clin. Invest. 47: 1045-1052.
3) Small, D.M., G.G. Shipley. 1974. Physical-chemical basis of lipid deposition in atherosclerosis. Science 185:222-229.
4) Deckelbaum, R.J., G.G. Shipley, D.M. Small, R.S. Lees, P.K. George. 1975. Thermal transitions in human plasma low density lipoproteins. Science, 190:392-394.
5) Tall, A.R., D.M. Small, G.G.Shipley, R.S. Lees. 1975. Apoprotein stability and lipid-protein interaction in human plasma high density lipoproteins. Proc.Natl. Acad. Sci. USA. 72: 4940-4942.
6) Herscovitz, Haya, A. Kritis, I. Talianidis, E. Zannis, V. Zannis and D.M. Small. 1995. Murine mammary-derived cells secrete the N-terminal 41% of human apolipoprotein B on high density lipoprotein-sized lipoproteins containing triacylglycerol-rich core. Proc. Natl. Acad. Sci. USA. 92:659-663. PMID: 7846033. PMCID: PMC42679
7) McNamara, J. D.M. Small, Zhenling Li, E.J. Schaefer. 1996. Differences in LDL subspecies involve alterations in lipid composition and conformational changes in apolipoprotein B. J. Lipid Res. 37: 1924-35.
8) Gantz,DL., M.T. Walsh and D.M. Small. Morphology of Sodium Deoxycholate-solubilized Apolipoprotein B100 (ApoB100) using Negative Stain and Vitreous Ice Electron Microscopy. 2000. J. Lipid Res. 41: 1464-1472. PMID: 10974054. pMCID in progress.
9) Carraway, M., H. Herscovitz, V. Zannis and D.M. Small. 2000. The Specificity of Lipid Incorporation is Determined by Sequences in the N-Terminal 37% of ApoB. Biochemistry. 39:9737-9745. PMID:10933790
10) Libo Wang, D. Atkinson and D.M. Small. 2003. Interfacial properties of an Amphipathic a-Helix Consensus Peptide of Exchangeable Apolipoproteins at Air/Water and Oil/Water Interfaces. JBC. 278: 37480-37491. PMID: 12842901. PMCID in progress.
11) Wang, L., and D.M. Small. 2004. Interfacial properties of amphipathic beta strand consensus peptides of apolipoprotein B at oil/water interfaces. JLR. 45:1704-1715. PMID: 15231853.
12) Wang,, L.,, D.A. Atkinson and D.M. Small. 2005. Interfacial properties of apoA-1 and CSP-an amphipathic a-helical consensus peptide of exchangeable apolipoprotein at triolein/water interface. JBC. 280(6):4154-4165. PMID: 15695525. PMCID in progress.
13) Wang, L., Walsh M.T. and Small D.M.. 2006. Apolipoprotein B is conformationally flexible but anchored at a triolein/water Interface: A possible model for lipoprotein surfaces. PNAS, 103(18): 6871-6876. PMID:16636271. PMCID; PMC1458986.
14) Wang, L., Ning H., Atkinson D. and Small D.M. 2007. The N-(1-44) and C-terminal (198-243) peptides of apoA-1 behave differently at the triolein/water interface. Biochemistry. 46(43): 12140-12151. PMID: 17915945. PMCID in progress.
15) Mitsche M.A., L. Wang, Z. G. Jiang, C.J. McKnight and D.M. Small. Interfacial Properties of a Complex Multi-Domain 490 Amino Acid Peptide Derived from Apolipoprotein B (Residues 292-782). 2008. Langmuir. 24(4):2322-2330. PMID: 19146422. PMCID in progress.
16) Wang L., D.D. Martin, E. Genter, J. Wang, R.S. McLeod and D.M. Small. Surface study of the apoB1694-1890, a sequence that can anchor apoB to lipoproteins and make it nonexchangeable. 2009. JLR. 50: 1340-1352. PMID: 19251580. PMCID: PMC2694333.
17) *Small D.M., L. Wang and M. Mitsche, The adsorption of biological peptides and proteins at the oil/water interface. A potentially important but largely unexplored field. JLR, 50th Ann. Issue, 2009, S329-334. PMID: 19029067. PMCID in progress.
18. Mitsche, Matthew, Wang L., Small, D.M., (2010). Adsorption of Egg-PC to an Air/Water and Triolein/Water bubble Interface: Use of the 2-Dimensional Phase Rule to Estimate the Surface Composition of a Phospholipid/Triolein/Water Surface as a Function of Surface Pressure. The Journ. Phys. Chem. Accepted DOI: 10.1021/JP908730t. PMCID in progress.
Department of Physiology and Biophysics
Boston University School of Medicine
700 Albany Street
Boston MA 02118-2526
Fax: (617) 638-4041