Effects of Protein Oxidation on the Structure and Stability of Model Discoidal High-Density Lipoproteins

Jayaraman, Sundararajan; Gantz, Donald; Gursky, Olga

doi:10.1021/bi7023783

Cited by 38 publications

(34 citation statements)

References 50 publications

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“…Less salt-bridges pair the protein strands in the spherical HDL particle than in the discoidal HDL particle, the latter exhibiting about 18 salt-bridges (as measured from all-atom simulations of discoidal HDL reported in Shih et al (2005)). Apparently, breakage of salt-bridges is necessary during maturation of HDL, which is consistent with observations that oxidation of HDL particles leads to enhanced conversion of discoidal to spherical HDL (Jayaraman et al, 2008). In Catte et al (2008), all-atom simulations of smaller spherical HDL particles were reported to contain between 10 and 12 salt-bridges.…”

Section: Resultssupporting

confidence: 90%

Maturation of high-density lipoproteins

Shih

Sligar

Schulten

2009

J. R. Soc. Interface.

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Human high-density lipoproteins (HDLs) are involved in the transport of cholesterol. The mechanism by which HDL assembles and functions is not well understood owing to a lack of structural information on circulating spherical HDL. Here, we report a series of molecular dynamics simulations that describe the maturation of discoidal HDL into spherical HDL upon incorporation of cholesterol ester as well as the resulting atomic level structure of a mature circulating spherical HDL particle. Sixty cholesterol ester molecules were added in a stepwise fashion to a discoidal HDL particle containing two apolipoproteins wrapped around a 160 dipalmitoylphosphatidylcholine lipid bilayer. The resulting matured particle, captured in a coarse-grained description, was then described in a consistent all-atom representation and analysed in chemical detail. The simulations show that maturation results from the formation of a highly dynamic hydrophobic core comprised of cholesterol ester surrounded by phospholipid and protein; the two apolipoprotein strands remain in a belt-like conformation as seen in the discoidal HDL particle, but with flexible N-and C-terminal helices and a central region stabilized by salt bridges. In the otherwise flexible lipoproteins, a less mobile central region provides an ideal location to bind lecithin cholesterol acyltransferase, the key enzyme that converts cholesterol to cholesterol ester during HDL maturation.

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Section: Resultssupporting

confidence: 90%

Maturation of high-density lipoproteins

Shih

Sligar

Schulten

2009

J. R. Soc. Interface.

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“…Few studies investigated the influence of HOCl-treatment on protein activity, and only a very select number of investigations dealt with the potential influence of low concentrations of HOCl on the folding status of proteins (Hawkins and Davies, 2005; Jayaraman et al, 2008). Our results indicated that low HOCl to protein ratios cause the unfolding of Hsp33 in vitro .…”

Section: Resultsmentioning

confidence: 99%

Bleach Activates a Redox-Regulated Chaperone by Oxidative Protein Unfolding

Winter

Ilbert

Graf

et al. 2008

Cell

349

373

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Summary Hypochlorous acid (HOCl), the active ingredient of household bleach, is an effective antimicrobial produced by the mammalian host defense to kill invading microorganisms. Despite the widespread use of HOCl, surprisingly little is known about its mode of action. In this study we demonstrate that low molar ratios of HOCl to protein cause oxidative protein unfolding in vitro and target thermolabile proteins for irreversible aggregation in vivo. As a defense mechanism, bacteria employ the redox-regulated chaperone Hsp33, which responds to bleach treatment with the reversible oxidative unfolding of its C-terminal redox switch domain. HOCl-mediated unfolding turns inactive Hsp33 into a highly active chaperone holdase, which protects essential E. coli proteins against HOCl-induced aggregation and increases bacterial HOCl-resistance. Our results substantially improve our molecular understanding about HOCl’s functional mechanism. They suggest that the antimicrobial effects of bleach are largely based on HOCl’s ability to cause aggregation of essential bacterial proteins.

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“…Oxidized proteins have often been reported to have reduced bioactivity, [30][31][32][33] to play a role in several diseases [34][35][36][37] and to influence protein aggregation and conformation. 38,39 It has also been reported that oxidation can create problems during downstream processing. 40 In these studies, obtaining large quantities of naturally oxidized proteins can be an issue.…”

Section: Discussionmentioning

confidence: 99%