Dr. Small founded of the Department of Biophysics at Boston University School of Medicine and served as its Chair form 1988 to 2000. After 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 a/?-?1-a1-?2-a2 secondary structure. In 1997, Drs. Small and Atkinson presented a more detailed model for the ?1 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 ? 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 ?1 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 phosphatdylcholine (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.
- Graduate Faculty (Primary Mentor of Grad Students), Boston University School of Medicine, Graduate Medical Sciences
- Professor, Biochemistry, Boston University School of Medicine
- Professor, Medicine, Boston University School of Medicine
- University of California, Los Angeles, MD
- University of Oxford, AM
- University of Oxford, AB
- Occidental College, BA
- Published on 2/3/2017
Meyers NL, Larsson M, Vorrsjö E, Olivecrona G, Small DM. Aromatic residues in the C terminus of apolipoprotein C-III mediate lipid binding and LPL inhibition. J Lipid Res. 2017 May; 58(5):840-852. PMID: 28159869.
- Published on 5/29/2015
Meyers NL, Larsson M, Olivecrona G, Small DM. A Pressure-dependent Model for the Regulation of Lipoprotein Lipase by Apolipoprotein C-II. J Biol Chem. 2015 Jul 17; 290(29):18029-44. PMID: 26026161.
- Published on 4/18/2014
Heiser D, Tan YS, Kaplan I, Godsey B, Morisot S, Cheng WC, Small D, Civin CI. Correlated miR-mRNA expression signatures of mouse hematopoietic stem and progenitor cell subsets predict "Stemness" and "Myeloid" interaction networks. PLoS One. 2014; 9(4):e94852. PMID: 24747944.
- Published on 2/10/2014
Mitsche MA, Packer LE, Brown JW, Jiang ZG, Small DM, McKnight CJ. 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. 2014 Mar 28; 289(13):9000-12. PMID: 24515109.
- Published on 1/16/2014
Kats LM, Reschke M, Taulli R, Pozdnyakova O, Burgess K, Bhargava P, Straley K, Karnik R, Meissner A, Small D, Su SM, Yen K, Zhang J, Pandolfi PP. Proto-oncogenic role of mutant IDH2 in leukemia initiation and maintenance. Cell Stem Cell. 2014 Mar 6; 14(3):329-41. PMID: 24440599.
- 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 5/13/2013
Meyers NL, Wang L, Gursky O, Small DM. Changes in helical content or net charge of apolipoprotein C-I alter its affinity for lipid/water interfaces. J Lipid Res. 2013 Jul; 54(7):1927-38. PMID: 23670531.
- Published on 3/25/2013
Mitsche MA, Small DM. Surface pressure-dependent conformation change of apolipoprotein-derived amphipathic a-helices. J Lipid Res. 2013 Jun; 54(6):1578-88. PMID: 23528259.
- Published on 9/6/2012
Kim KT, Carroll AP, Mashkani B, Cairns MJ, Small D, Scott RJ. MicroRNA-16 is down-regulated in mutated FLT3 expressing murine myeloid FDC-P1 cells and interacts with Pim-1. PLoS One. 2012; 7(9):e44546. PMID: 22970245.
- Published on 5/1/2012
McCall CM, Mudali S, Arceci RJ, Small D, Fuller S, Gocke CD, Vuica-Ross M, Burns KH, Borowitz MJ, Duffield AS. Flow cytometric findings in hemophagocytic lymphohistiocytosis. Am J Clin Pathol. 2012 May; 137(5):786-94. PMID: 22523218.
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