Assembly of Lipids and Proteins into Lipoprotein Particles

Shih, Amy Y.; Arkhipov, Anton; Freddolino, Peter L.; Sligar, Stephen G.; Schulten, Klaus

doi:10.1021/jp072320b

Cited by 63 publications

(75 citation statements)

References 89 publications

(240 reference statements)

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“…They substantiated their findings by preparing rHDL with DPPC (or DMPC) and truncated apoA-I lacking residues 1-54. Experimental SAXS measurements were similar to the theoretically calculated values and gave diameters in the range of 102 Å to 103 Å (93).…”

Section: Dynamic Simulationssupporting

confidence: 75%

“…These studies directly address the question of how lipid-poor apoA-I structure adapts to increased phospholipid content, e.g., as apoA-I is lipidated by ABCA1 (89)(90)(91)(92)(93). Using a mutant form of apoA-I lacking the N-terminal amino acids 1-40, Catte et al (92) reported an extensive in silico investigation of the relationship between the lipid-to-apoA-I molar ratio and apoA-I conformation.…”

Section: Dynamic Simulationsmentioning

confidence: 99%

See 1 more Smart Citation

Three-dimensional models of HDL apoA-I: implications for its assembly and function

Thomas

Bhat

Sorci‐Thomas

2008

Journal of Lipid Research

109

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The purpose of this review is to highlight recent advances toward the refinement of a three-dimensional structure for lipid-bound apolipoprotein A-I (apoA-I) on recombinant HDL. Recently, X-ray crystallography has yielded a new structure for full-length, lipid-free apoA-I. Although this approach has not yet been successful in solving the threedimensional structure of lipid-bound apoA-I, analysis of the X-ray structures has been of immense help in the interpretation of structural data obtained from other methods that yield structural information. Recent studies emphasize the use of mass spectrometry to unambiguously identify crosslinked peptides or to quantify solvent accessibility using hydrogen-deuterium exchange. The combination of mass spectrometry, molecular modeling, molecular dynamic analysis, and small-angle X-ray diffraction has provided additional structural information on apoA-I folding that complements previous approaches. To understand the mechanism of HDL apolipoprotein A-I (apoA-I) protection against the development of coronary heart disease, recent investigations have focused on apoA-Iʼs dual functions in promoting lipid efflux (1-4) and its role in modulating immune cell activation (5-10). Recent attention has now focused on elucidating the threedimensional conformation of apoA-I, the most abundant protein constituent within the HDL particle, in response to its acquisition of phospholipid and cholesterol to form nascent lipoprotein particles.ApoA-I is a 28 kDa protein synthesized by the liver and small intestine. It plays a key role in the formation, metabolism, and catabolism of HDL, a plasma lipoprotein whose levels are highly linked to protection against the development of coronary artery disease, even in patients with very low LDL cholesterol levels (11). Formation of plasma HDL particles depends entirely on the initial lipidation of apoA-I by ABCA1 (12-14). Dimers of lipid-free or lipid-poor apoA-I acquire limited amounts of phospholipid and cholesterol from the membrane-bound ABCA1 transporter to form one of several classes of nascent HDL particles (15). Other classes of nascent HDL particles formed from this interaction contain more than two molecules of apoA-I per particle, with increased amounts of phospholipid and cholesterol (16)(17)(18).A second lipidation step essential for plasma HDL maturation is the activation of the enzyme LCAT by lipid-bound apoA-I. Activation of this enzyme results in the synthesis of cholesteryl esters on nascent HDL (19), providing a hydrophobic core and transforming the small, lipid-poor particle to a spherical lipid-rich HDL. Studies of human deficiencies have shown that if either ABCA1 or LCAT are inactive, plasma concentrations of HDL apoA-I are very low, owing to the rapid removal of the small lipid-poor HDL apoA-I from circulation (20,21). Thus, both of these two major apoA-I lipidation steps are absolutely essential for the formation of mature spherical plasma HDL and, to some extent, the functionality of the HDLs themselves (22-24).ApoA-I has...

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Section: Dynamic Simulationssupporting

confidence: 75%

Section: Dynamic Simulationsmentioning

confidence: 99%

Three-dimensional models of HDL apoA-I: implications for its assembly and function

Thomas

Bhat

Sorci‐Thomas

2008

Journal of Lipid Research

109

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“…Although the detailed topography of protein and lipid components remained undefined, the authors concluded that the protein of HDL is located circumferentially relative to lipid within the particle and suggested a bilayer disk (oblate ellipsoid) model for HDL. Additional studies on reconstituted HDL performed by SAXS without contrast variation and molecular dynamics simulations (67,68) either lent support to the idea of HDL being discoidal or did not define a low resolution model of nascent HDL with contrast variation. In preliminary SANS studies, we similarly could not define the low resolution shape of apoA-I within HDL because of both a weak protein signal and the overlap between the scattering signal from protein and phospholipid at higher angles.…”

Section: Discussionmentioning

confidence: 96%

Double Superhelix Model of High Density Lipoprotein

Gogonea

Lee

et al. 2009

Journal of Biological Chemistry

175

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High density lipoprotein (HDL), the carrier of so-called "good" cholesterol, serves as the major athero-protective lipoprotein and has emerged as a key therapeutic target for cardiovascular disease. We applied small angle neutron scattering (SANS) with contrast variation and selective isotopic deuteration to the study of nascent HDL to obtain the low resolution structure in solution of the overall time-averaged conformation of apolipoprotein AI (apoA-I) versus the lipid (acyl chain) core of the particle. Remarkably, apoA-I is observed to possess an open helical shape that wraps around a central ellipsoidal lipid phase. Using the low resolution SANS shapes of the protein and lipid core as scaffolding, an all-atom computational model for the protein and lipid components of nascent HDL was developed by integrating complementary structural data from hydrogen/deuterium exchange mass spectrometry and previously published constraints from multiple biophysical techniques. Both SANS data and the new computational model, the double superhelix model, suggest an unexpected structural arrangement of protein and lipids of nascent HDL, an anti-parallel double superhelix wrapped around an ellipsoidal lipid phase. The protein and lipid organization in nascent HDL envisages a potential generalized mechanism for lipoprotein biogenesis and remodeling, biological processes critical to sterol and lipid transport, organismal energy metabolism, and innate immunity. High density lipoprotein (HDL)2 functions in removal of cholesterol from peripheral tissues, such as within the artery wall, for delivery to the liver and ultimate excretion as biliary cholesterol within the intestinal lumen, a process called reverse cholesterol transport (1, 2). Plasma levels of HDL cholesterol and apolipoprotein AI (apoA-I), the major protein component of HDL, are inversely related to the risk of developing coronary artery disease (3-5). Moreover, genetic alterations that induce changes in apoA-I levels in both animals and humans alter susceptibility for development of atherosclerotic heart disease (3-6). Thus, numerous interventions aimed at enhancing reverse cholesterol transport are being examined as potential novel therapeutic interventions for the prevention and treatment of cardiovascular disease (7,8). Examples include methods for generating new HDL particles through enhanced production or delivery of either intact apoA-I (9, 10) or peptide mimetics of apoA-I (11), as well as modulating interactions between nascent HDL and proteins involved in HDL particle maturation and remodeling for potential therapeutic benefit (12-14). Structural elucidation often serves as the "Rosetta Stone" for enhanced understanding of function. It is thus remarkable that despite its importance to numerous biological and biomedical functions and its current prominent role as a target for therapeutic interventions, to date, the structures of neither the protein nor lipid components of nascent HDL have been directly visualized, and the high resolution structure of the particl...

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“…While, to our knowledge there are only a few reported molecular simulation studies of SMALPS nanodiscs to date (two papers not discussed here are 54,55 ), the field of nanoparticle simulation in general is growing at a rapid rate. Numerous studies of the interaction of fullerenes, carbon nanotubes, and dendrimers with lipid bilayers have been published in the last few years [56][57][58][59][60] .…”

Section: Opportunity For Use In Molecular Simulationmentioning

confidence: 99%

Encapsulated membrane proteins: A simplified system for molecular simulation

Lee¹,

Khalid²,

Pollock³

et al. 2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 2Over the past 50 years there has been considerable progress in our understanding of biomolecular interactions at an atomic level. This in turn has allowed molecular simulation methods employing full atomistic modeling at ever larger scales to develop. However, some challenging areas still remain where there is either a lack of atomic resolution structures or where the simulation system is inherentlycomplex.An area where both challenges are present is that of membranes containing membrane proteins. In this review we analyse a new practical approach to membrane protein study that offers a potential new route to high resolution structures and the possibility to simplify simulations.These new approaches collectively recognise that preservation of the interaction between the membrane protein and the lipid bilayer is often essential to maintain structure and function. The new methods preserve these interactions by producing nano-scale disc shaped particles that include bilayer and the chosen protein. Currently two approaches lead in this area: the MSP system that relies on peptides to stabilise the discs, and SMALPs where an amphipathic styrene maleic acid copolymer is used. Both methods greatly enable protein production and hence have the potential to accelerate atomic resolution structure determination as well as providing a simplified format for simulations of membrane protein dynamics.

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Assembly of Lipids and Proteins into Lipoprotein Particles

Cited by 63 publications

References 89 publications

Three-dimensional models of HDL apoA-I: implications for its assembly and function

Three-dimensional models of HDL apoA-I: implications for its assembly and function

Double Superhelix Model of High Density Lipoprotein

Encapsulated membrane proteins: A simplified system for molecular simulation

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