Olga. Gursky

Olga. Gursky
Boston University | BU · Department of Physiology and Biophysics

PhD, Brandeis University

About

115
Publications
12,785
Reads
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2,434
Citations
Additional affiliations
January 2000 - December 2012
Boston University Medical Campus
November 1994 - present
Boston University
September 1988 - October 1994
Education
September 1988 - June 1991
Brandeis University
Field of study
  • Physics / Structural Biology
September 1977 - January 1983

Publications

Publications (115)
Article
Full-text available
Oxidative stress and inflammation, which involves a dramatic increase in serum amyloid A (SAA) levels, are critical in the development of atherosclerosis. Most SAA circulates on plasma HDL particles, altering their cardioprotective properties. SAA-enriched HDL have diminished anti-oxidant effects on LDL, which may contribute to atherogenesis. We de...
Article
Serum amyloid A is a major acute-phase plasma protein that modulates innate immunity and cholesterol homeostasis. We combine sequence analysis with x-ray crystal structures to postulate that SAA acts as an intrinsically disordered hub mediating interactions among proteins, lipids and proteoglycans. A structural model of lipoprotein-bound SAA monome...
Article
ApoA-I, the major protein of plasma high-density lipoprotein, removes cellular cholesterol and protects against atherosclerosis. ApoA-I mutations can cause familial amyloidosis, a life-threatening disease wherein N-terminal protein fragments form fibrils in vital organs. To unveil the protein misfolding mechanism and to understand why some mutation...
Article
Apolipoproteins are protein constituents of lipoproteins that transport cholesterol and fat in circulation and are central to cardiovascular health and disease. Soluble apolipoproteins can transiently dissociate from the lipoprotein surface in a labile free form that can misfold, potentially leading to amyloid disease. Misfolding of apoA-I, apoA-II...
Article
Lipoproteins are protein-lipid nanoparticles that transport lipids in circulation and are central in atherosclerosis and other disorders of lipid metabolism. Apolipoproteins form flexible structural scaffolds and important functional ligands on the particle surface and direct lipoprotein metabolism. Lipoproteins undergo multiple rounds of metabolic...
Article
Hydrolysis of VLDL triacylglycerol (TG) by lipoprotein lipase (LpL) is a major step in energy metabolism and VLDL-to-LDL maturation. Most functional LpL is anchored to the vascular endothelium, yet a small amount circulates on TG-rich lipoproteins. As circulating LpL has low catalytic activity, its role in VLDL remodeling is unclear. We use pre-hep...
Article
Dynamic and disordered regions in native proteins are often critical for their function, particularly in ligand binding and signaling. In certain proteins, however, such regions can contribute to misfolding and pathologic deposition as amyloid fibrils in vivo. For example, dynamic and disordered regions can promote amyloid formation by destabilizin...
Article
Immunoglobulin light chain (LC) amyloidosis (AL) is a life-threatening human disease wherein free monoclonal LCs deposit in vital organs. To determine what makes some LCs amyloidogenic, we explored patient-based amyloidogenic and non-amyloidogenic recombinant LCs from the λ 6 subtype prevalent in AL. Hydrogen-deuterium exchange mass spectrometry, s...
Article
Recent advances in high-resolution structural studies of protein amyloids have revealed parallel in-register cross-β-sheets with periodic arrays of closely spaced identical residues. What do these structures tell us about the mechanisms of action of common amyloid-promoting factors, such as heparan sulfate (HS), nucleic acids, polyphosphates, anion...
Article
Full-text available
Purpose of review: This review addresses normal and pathologic functions of serum amyloid A (SAA), an enigmatic biomarker of inflammation and protein precursor of AA amyloidosis, a life-threatening complication of chronic inflammation. SAA is a small, highly evolutionarily conserved acute-phase protein whose plasma levels increase up to one thousa...
Article
Full-text available
Amyloidoses are life-threatening diseases caused by the deposition of various proteins including apolipoprotein A-I, the major protein of plasma high-density lipoprotein. Timely diagnostics of amyloidoses are crucial for their treatment. Colombat et al. reported novel aspects of the hereditary apolipoprotein A-I amyloidosis, including its unexpecte...
Article
Low-density lipoprotein (LDL) binding to arterial proteoglycans initiates LDL retention and modification in the arterial wall, triggering atherosclerosis. The details of this binding, its effectors, and its ramifications are incompletely understood. We combined heparin affinity chromatography with biochemical, spectroscopic and electron microscopic...
Article
Serum amyloid A (SAA) is a plasma protein that transports lipids during inflammation. To explore SAA solution conformations and lipid binding mechanism, we used hydrogen-deuterium exchange mass spectrometry, lipoprotein reconstitution, amino acid sequence analysis and molecular dynamics simulations. Solution conformations of lipid-bound and lipid-f...
Article
Full-text available
Serum amyloid A (SAA) is an evolutionally conserved enigmatic biomarker of inflammation. In acute inflammation, SAA plasma levels increase ~1,000-fold suggesting a vital beneficial role. SAA increases simultaneously with secretory phospholipase A2 (sPLA2), compelling us to determine how SAA influences sPLA2 hydrolysis of lipoproteins. SAA solubiliz...
Article
Very low-density lipoprotein (VLDL) is the main plasma carrier of triacylglycerol that is elevated in pathological conditions such as diabetes, metabolic syndrome, obesity and dyslipidemia. How variations in triacylglycerol levels influence structural stability and remodeling of VLDL and its metabolic product, low-density lipoproteins (LDL), is unk...
Article
Hereditary apolipoprotein A-I (apoA-I) amyloidosis is a life-threatening incurable genetic disorder whose molecular underpinnings are unclear. In this disease, variant apoA-I, the major structural and functional protein of high-density lipoprotein, is released in a free form, undergoes an alpha-helix to intermolecular cross-beta-sheet conversion al...
Article
Plasma high-density lipoproteins (HDLs) are protein–lipid nanoparticles that transport lipids and protect against atherosclerosis. Human apolipoprotein A-I (apoA-I) is the principal HDL protein whose mutations can cause either aberrant lipid metabolism or amyloid disease. Hydrogen–deuterium exchange (HDX) mass spectrometry (MS) was used to study th...
Article
Full-text available
Transthyretin (TTR) is a globular tetrameric transport protein in plasma. Nearly 140 single amino acid substitutions in TTR cause life-threatening amyloid disease. We report a one-of-a-kind pathological variant featuring a Glu51, Ser52 duplication mutation (Glu51_Ser52dup). The proband, heterozygous for the mutation, exhibited an unusually aggressi...
Preprint
Full-text available
Hereditary apolipoprotein A-I (apoA-I) amyloidosis (AApoAI) is a life-threatening incurable genetic disorder whose molecular underpinnings and the full spectrum of afflicted organs are unclear. We report a new form of AApoAI with amyloid deposition in multiple organs, including an unprecedented retinal amyloidosis. Genetic and proteomic analyses id...
Article
Full-text available
Serum amyloid A action in immune response and deposition in inflammation-linked amyloidosis involve SAA-lipid interactions. We show that SAA sequesters neutral and anionic phospholipids and their hydrolytic products to form...
Article
Full-text available
Chlamydia is the most common cause of bacterial sexually transmitted infections worldwide. While infections resolve with antibiotic treatment, this is often neglected in women due to frequent asymptomatic infections, leading to disease progression and severe sequelae (pelvic inflammatory disease, ectopic pregnancy, infertility). Development of a va...
Data
Primer sequences for polymerase chain reaction amplification of APOA2 gene.
Article
Full-text available
Here, we report a family with renal amyloidosis associated with a novel stop codon mutation in APOA2 and the apoA-II variant, 78Leuext21.
Article
Full-text available
Serum amyloid A (SAA) is an acute-phase plasma protein that functions in innate immunity and lipid homeostasis. SAA is a protein precursor of reactive AA amyloidosis, the major complication of chronic inflammation and one of the most common human systemic amyloid diseases worldwide. Most circulating SAA is protected from proteolysis and misfolding...
Article
Full-text available
Immunoglobulin (Ig) light chain (LC) amyloidosis (AL) is characterized by the overproduction and tissue deposition of monoclonal LC in various organs and tissues. The plasma circulating monoclonal LC is believed to be the precursor of the deposited protein and in vitro studies aimed at understanding AL pathobiology have mainly focused on LC and its...
Article
Serum amyloid A (SAA) is an acute-phase protein whose action in innate immunity and lipid homeostasis is unclear. Most circulating SAA binds plasma high-density lipoproteins (HDL) and reroutes lipid transport. In vivo SAA binds existing lipoproteins or generates them de novo upon lipid uptake from cells. We explored the products of SAA-lipid intera...
Article
Lipids in the body are transported via lipoproteins that are nanoparticles comprised of lipids and amphipathic proteins termed apolipoproteins. This family of lipid surface-binding proteins is over-represented in human amyloid diseases. In particular, all major proteins of high-density lipoproteins (HDL), including apoA-I, apoA-II and serum amyloid...
Article
Low-density lipoprotein (LDL) aggregation is central in triggering atherogenesis. A minor fraction of electronegative plasma LDL, termed LDL(−), plays a special role in atherogenesis. To better understand this role, we analyzed the kinetics of aggregation, fusion and disintegration of human LDL and its fractions, LDL(+) and LDL(−). Thermal denatura...
Article
Full-text available
Serum amyloid A (SAA) is an acute-phase protein that circulates mainly on plasma high-density lipoprotein (HDL). SAA interactions with its functional ligands and its pathogenic deposition in reactive amyloidosis depend, in part, on the structural disorder of this protein and its propensity to oligomerize. In vivo, SAA can displace substantial fract...
Book
This book addresses molecular mechanisms of protein misfolding and the role of lipids and related molecules in these complex processes. The focus is on the biophysical and structural studies of proteins that are involved in major human disorders such as Alzheimer’s disease, systemic amyloidoses, diabetes II, inflammation and atherosclerosis. Misfol...
Article
Full-text available
High-density lipoproteins (HDLs) and their major protein, apoA-I, remove excess cellular cholesterol and protect against atherosclerosis. However, in acquired amyloidosis, non-variant full-length apoA-I deposits as fibrils in atherosclerotic plaques; in familial amyloidosis, N-terminal fragments of variant apoA-I deposit in vital organs damaging th...
Article
ApoA-II is the second-major protein of high-density lipoproteins. C-terminal extension in human apoA-II or point substitutions in murine apoA-II cause amyloidosis. The molecular mechanism of apolipoprotein misfolding, from the native predominantly α-helical conformation to cross-β-sheet in amyloid, is unknown. We used 12 sequence-based prediction a...
Article
Full-text available
HDL remove cell cholesterol and protects against atherosclerosis. Apolipoprotein A-I provides a flexible structural scaffold and an important functional ligand on the HDL surface. We propose structural models for apoA-IMilano (R173C) and apoA-IParis (R151) mutants that show high cardioprotection despite low HDL levels. Previous studies established...
Article
Full-text available
Low-density lipoproteins (LDLs, also known as ' bad cholesterol ') are the major carriers of circulat-ing cholesterol and the main causative risk factor of atherosclerosis. Plasma LDLs are 20-to 25-nm nanopar-ticles containing a core of cholesterol esters surrounded by a phospholipid monolayer and a single copy of apoli-poprotein B (550 kDa). An ea...
Article
Full-text available
Amphipathic α-helices mediate binding of exchangeable apolipoproteins to lipoproteins. To probe the role of α-helical structure in protein-lipid interactions, we used oil-drop tensiometry to characterize the interfacial behavior of apolipoprotein C-I (apoC-I) variants at triolein/water (TO/W) and 1-palmitoyl-2-oleoylphosphatidylcholine/triolein/wat...
Article
Full-text available
Fusion of modified LDL in the arterial wall promotes atherogenesis. Earlier we showed that thermal denaturation mimics LDL remodeling and fusion, and revealed kinetic origin of LDL stability. Here we report the first quantitative analysis of LDL thermal stability. Turbidity data show sigmoidal kinetics of LDL heat denaturation, which is unique amon...
Article
High-density lipoproteins (HDL, or "good cholesterol") are heterogeneous nanoparticles that remove excess cell cholesterol and protect against atherosclerosis. The cardioprotective action of HDL and its major protein, apolipoprotein A-I (apoA-I), is well-established, yet the function of the second major protein, apolipoprotein A-II (apoA-II), is le...
Article
Full-text available
Apolipoprotein A-I (apoA-I) is the main protein of plasma high-density lipoproteins (HDL, or good cholesterol) that remove excess cell cholesterol and protect against atherosclerosis. In hereditary amyloidosis, mutations in apoA-I promote its proteolysis and the deposition of the 9-11 kDa N-terminal fragments as fibrils in vital organs such as kidn...
Chapter
Full-text available
Lipoproteins are water-soluble non-covalent assemblies comprised of several proteins (termed apolipoproteins) and several hundred lipid molecules. These assemblies mediate transport and metabolism of lipids and are central to the development of major human diseases, most notably atherosclerosis. Plasma lipoproteins are divided into classes accordin...
Article
Full-text available
HDL (high-density lipoproteins) remove cell cholesterol and protect from atherosclerosis. The major HDL protein is apoA-I (apolipoprotein A-I). Most plasma apoA-I circulates in lipoproteins, yet ~5% forms monomeric lipid-poor/free species. This metabolically active species is a primary cholesterol acceptor and is central to HDL biogenesis. Structur...
Data
Full-text available
The supplementary material includes the melting data illustrating the destabilizing effects of TRIS on VLDL assembly and the effect of salt on LDL stability.
Article
Full-text available
Very low-density lipoproteins (VLDL) are precursors of low-density lipoproteins (LDL, or "bad cholesterol"). Factors affecting structural integrity of VLDL are important for their metabolism. To assess the role of electrostatic interactions in VLDL stability, we determined how solvent ionic conditions affect the heat-induced VLDL remodeling. This r...
Article
Full-text available
Hydrolysis and oxidation of LDL stimulate LDL entrapment in the arterial wall and promote inflammation and atherosclerosis via various mechanisms including lipoprotein fusion and lipid droplet formation. To determine the effects of FFA on these transitions, we hydrolyzed LDL by phospholipase A(2) (PLA(2)), removed FFA by albumin, and analyzed struc...
Article
Plasma lipoproteins are assemblies of lipids and apolipoproteins that mediate lipid transport and metabolism. High-density lipoproteins (HDL) remove excess cell cholesterol and provide protection against atherosclerosis. Important aspects of metabolic HDL remodeling, including apolipoprotein dissociation and lipoprotein fusion, are mimicked in ther...
Article
Very low density lipoproteins (VLDL) are triglyceride-rich precursors of low-density lipoproteins (LDL) and a risk factor for atherosclerosis. The effects of oxidation on VLDL metabolism may be pro- or antiatherogenic. To understand the underlying biophysical basis, we determined the effects of copper (that preferentially oxidizes lipids) and hypoc...
Article
Light chain (LC) amyloidosis (AL) is a fatal disease in which immunoglobulin LC deposit as fibrils. Although the LC amyloid-forming propensity is attributed primarily to the variable region, fibrils also contain full-length LC comprised of variable-joining (V(L)) and constant (C(L)) regions. To assess the role of C(L) in fibrillogenesis, we compare...
Article
High-density lipoproteins (HDLs) are complexes of lipids and proteins (termed apolipoproteins) that remove cell cholesterol and protect from atherosclerosis. Apolipoproteins contain amphipathic alpha-helices that have high content (> or = 1/3) and distinct distribution of charged and apolar residues, adopt molten globule-like conformations in solut...
Article
Full-text available
Reverse cholesterol transport in plasma involves variations in HDL cholesterol concentration. To understand physicochemical and functional implications of such variations, we analyzed stability of reconstituted HDL containing human apolipoproteins (apoA-I, apoA-II, or apoC-I), phosphatidylcholines varying in chain length (12-18 carbons) and unsatur...