Global Structure and Dynamics of Human Apolipoprotein CII in Complex with Micelles:  Evidence for Increased Mobility of the Helix Involved in the Activation of Lipoprotein Lipase<sup>,</sup>

Zdunek, Janusz; Martinez, Gary V.; Schleucher, Jürgen; Lycksell, Per‐Olof; Yin, Yinliang; Nilsson, Solveig; Shen, Yan; Olivecrona, Gunilla; Wijmenga, Sybren S.

doi:10.1021/bi0267184

Cited by 52 publications

(73 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The NMR sample of apoCIII in complex with SDS micelles was prepared from lyophilized 15 N/ 13 C-labeled apoCIII as described (23), leading to the final ApoCIII-NMR sample: ϳ0.5 mM apoCIII, 180 mM SDS-d 25 , 8% D 2 O, and 10 mM deuterated sodium acetate buffer (pH 5.0). In this final sample, the apo-CIII/micelle ratio is 1:6, assuming 60 SDS molecules/micelle (23).…”

Section: Nmr Spectroscopy (A) Preparation Of Nmr Samples and Optimal mentioning

confidence: 99%

“…In this final sample, the apo-CIII/micelle ratio is 1:6, assuming 60 SDS molecules/micelle (23). For RDC measurements, we prepared a similar second sample (apoCIII-RDC), except for a slightly higher buffer concentration (50 mM).…”

Section: Nmr Spectroscopy (A) Preparation Of Nmr Samples and Optimal mentioning

confidence: 99%

“…For RDC measurements, we prepared a similar second sample (apoCIII-RDC), except for a slightly higher buffer concentration (50 mM). While keeping the apoCIII/SDS micelle ratio as low as possible (here 1:6) to prevent protein-protein interactions (23), relatively low SDS and buffer concentrations were used. This considerably reduced the overall tumbling time of the apoCIII-micelle complex and improved three-dimensional NMR spectra, as will be described elsewhere in more detail.…”

Section: Nmr Spectroscopy (A) Preparation Of Nmr Samples and Optimal mentioning

confidence: 99%

“…In the lipid-bound state, only recently the first low resolution (10 Å) x-ray model has been reported of an intact apolipoprotein, apoE (22). Also reported is the three-dimensional structure and dynamics of apoCII bound to micelles derived from NMR relaxation data (23). In addition, NMR has provided information on helix boundaries and local structure of lipidbound intact apoCII (24), apoCI (25), and apoAI (26).…”

mentioning

confidence: 99%

“…There is no consensus about which regions are most important for attachment to lipids (27)(28)(29). The structurally related apoCII is known to interact with LPL and activate this enzyme via the C-terminal helix (30), most likely in a dynamic fashion (23). ApoCIII inhibits LPL, but direct binding has not been shown (27).…”

mentioning

confidence: 99%

See 4 more Smart Citations

Structure and Dynamics of Human Apolipoprotein CIII

Gangabadage

Zdunek

Tessari

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

Human apolipoprotein CIII (apoCIII) is a surface component of chylomicrons, very low density lipoproteins, and high density lipoproteins. ApoCIII inhibits lipoprotein lipase as well as binding of lipoproteins to cell surface heparan sulfate proteoglycans and receptors. High levels of apoCIII are often correlated with elevated levels of blood lipids (hypertriglyceridemia). Here, we report the three-dimensional NMR structure and dynamics of human apo-CIII in complex with SDS micelles, mimicking its natural lipidbound state. Thanks to residual dipolar coupling data, the first detailed view is obtained of the structure and dynamics of an intact apolipoprotein in its lipid-bound state. ApoCIII wraps around the micelle surface as a necklace of six ϳ10-residue amphipathic helices, which are curved and connected via semiflexible hinges. Three positively charged (Lys) residues line the polar faces of helices 1 and 2. Interestingly, their three-dimensional conformation is similar to that of the low density lipoprotein receptor binding motifs of apoE/B and the receptor-associated protein. At the C-terminal side of apoCIII, an array of negatively charged residues lines the polar faces of helices 4 and 5 and the adjacent flexible loop. Sequence comparison shows that this asymmetric charge distribution along the solvent-exposed face of apoCIII as well as other structural features are conserved among mammals. This structure provides a template for exploration of molecular mechanisms by which human apoCIII inhibits lipoprotein lipase and receptor binding.Apolipoproteins consist of five major classes, apo-A 2 through -E, and several subclasses. They are designed for lipid transport in blood and are attached to lipid droplets (lipoproteins) through amphipathic helices that intercalate into the single layer of phospholipids and cholesterol covering the droplet (1-3). The apolipoproteins regulate blood lipid levels by interaction with specialized endocytotic receptors and by modulating enzyme activities and lipid exchange reactions (4). They are therefore in focus with regard to disturbances in blood lipid metabolism (dyslipidemias), which in turn are associated with metabolic disorders like obesity, insulin resistance, diabetes type 2, and cardiovascular disease.Apolipoprotein CIII (apoCIII) is the most abundant C-apolipoprotein in humans (2-4). It is found on very low density lipoproteins, chylomicrons, and high density lipoproteins (HDL). ApoCIII is predominantly expressed in liver and intestine from a gene cluster important for lipid regulation (ApoAI, -AIV, -AV, and -CIII) (4, 5). ApoCIII inhibits lipoprotein lipase (LPL) and receptor-mediated endocytosis of lipoprotein particles by competing for space at the surface of the lipoproteins and by interfering with their binding to endothelial proteoglycans and to specific lipoprotein receptors (2, 4, 6). Overexpression of apoCIII in transgenic mice leads to severely increased plasma triglyceride levels due to accumulation of very low density lipoprotein-like lipoprotein remnants w...

show abstract

Section: Nmr Spectroscopy (A) Preparation Of Nmr Samples and Optimal mentioning

confidence: 99%

Section: Nmr Spectroscopy (A) Preparation Of Nmr Samples and Optimal mentioning

confidence: 99%

Section: Nmr Spectroscopy (A) Preparation Of Nmr Samples and Optimal mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Structure and Dynamics of Human Apolipoprotein CIII

Gangabadage

Zdunek

Tessari

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

The Regulation of Triacylglycerol Metabolism and Lipoprotein Lipase Activity

2022

View full text Add to dashboard Cite

Triacylglycerol (TG) metabolism is tightly regulated to maintain a pool of TG within circulating lipoproteins that can be hydrolyzed in a tissue‐specific manner by lipoprotein lipase (LPL) to enable the delivery of fatty acids to adipose or oxidative tissues as needed. Elevated serum TG concentrations, which result from a deficiency of LPL activity or, more commonly, an imbalance in the regulation of tissue‐specific LPL activities, have been associated with an increased risk of atherosclerotic cardiovascular disease through multiple studies. Among the most critical LPL regulators are the angiopoietin‐like (ANGPTL) proteins ANGPTL3, ANGPTL4, and ANGPTL8, and a number of different apolipoproteins including apolipoprotein A5 (ApoA5), apolipoprotein C2 (ApoC2), and apolipoprotein C3 (ApoC3). These ANGPTLs and apolipoproteins work together to orchestrate LPL activity and therefore play pivotal roles in TG partitioning, hydrolysis, and utilization. This review summarizes the mechanisms of action, epidemiological findings, and genetic data most relevant to these ANGPTLs and apolipoproteins. The interplay between these important regulators of TG metabolism in both fasted and fed states is highlighted with a holistic view toward understanding key concepts and interactions. Strategies for developing safe and effective therapeutics to reduce circulating TG by selectively targeting these ANGPTLs and apolipoproteins are also discussed.

show abstract

How can a β‐sheet peptide be both a potent antimicrobial and harmfully toxic? Molecular dynamics simulations of protegrin‐1 in micelles

2005

View full text Add to dashboard Cite

In this work, the naturally occurring beta-hairpin antimicrobial peptide protegrin-1 (PG-1) is studied by molecular dynamics simulation in all-atom sodium dodecylsulfate and dodecylphosphocholine micelles. These simulations provide a high-resolution picture of the interactions between the peptide and simple models of bacterial and mammalian membranes. Both micelles show significant disruption, as is expected for a peptide that is both active against bacteria and toxic to host cells. There is, however, clear differentiation between the behavior in SDS versus DPC, which suggests different mechanisms of interaction for PG-1 with mammalian and bacterial membranes. Specifically, the equilibrium orientation of the peptide relative to SDS is a mirror image of its position relative to DPC. In both systems, the arginine residues of PG-1 strongly interact with the head groups of the micelles. In DPC, the peptide prefers a location closer to the core of the micelle with Phe12, Val14, and Val16 imbedded in the core and the other side of the hairpin, which includes Leu5 and Tyr7, located closer to the surface of the micelle. In SDS, the peptide prefers a location at the micelle-water interface. The peptide position is reversed, with Leu5 and Cys6 imbedded furthest in the micelle core and Phe12, Val14, and Val16 on the surface of the micelle. We discuss the implications of these results with respect to activity and toxicity.

show abstract

Global Structure and Dynamics of Human Apolipoprotein CII in Complex with Micelles: Evidence for Increased Mobility of the Helix Involved in the Activation of Lipoprotein Lipase^,

Cited by 52 publications

References 69 publications

Structure and Dynamics of Human Apolipoprotein CIII

Structure and Dynamics of Human Apolipoprotein CIII

The Regulation of Triacylglycerol Metabolism and Lipoprotein Lipase Activity

How can a β‐sheet peptide be both a potent antimicrobial and harmfully toxic? Molecular dynamics simulations of protegrin‐1 in micelles

Contact Info

Product

Resources

About

Global Structure and Dynamics of Human Apolipoprotein CII in Complex with Micelles: Evidence for Increased Mobility of the Helix Involved in the Activation of Lipoprotein Lipase,

Cited by 52 publications

References 69 publications

Structure and Dynamics of Human Apolipoprotein CIII

Structure and Dynamics of Human Apolipoprotein CIII

The Regulation of Triacylglycerol Metabolism and Lipoprotein Lipase Activity

How can a β‐sheet peptide be both a potent antimicrobial and harmfully toxic? Molecular dynamics simulations of protegrin‐1 in micelles

Contact Info

Product

Resources

About

Global Structure and Dynamics of Human Apolipoprotein CII in Complex with Micelles: Evidence for Increased Mobility of the Helix Involved in the Activation of Lipoprotein Lipase^,