The influence of cholesterol on membrane protein structure, function, and dynamics studied by molecular dynamics simulations

Grouleff, Julie; Irudayam, Sheeba Jem; Skeby, Katrine Kirkeby; Schiøtt, Birgit

doi:10.1016/j.bbamem.2015.03.029

Cited by 159 publications

(156 citation statements)

References 138 publications

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“…First, cholesterol may bind specifically with membrane proteins and thereby modulate their conformation and function, or cholesterol may modulate membrane physical properties to match the conditions that promote the activation of a given membrane protein. Related experimental 68, 69 and simulation 70–72 data are consistent with this view. Also, as discussed by Sodt et al .…”

Section: Discussionsupporting

confidence: 78%

Nanoscale Membrane Domain Formation Driven by Cholesterol

Javanainen

Martinez‐Seara

Vattulainen

2017

Sci Rep

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Biological membranes generate specific functions through compartmentalized regions such as cholesterol-enriched membrane nanodomains that host selected proteins. Despite the biological significance of nanodomains, details on their structure remain elusive. They cannot be observed via microscopic experimental techniques due to their small size, yet there is also a lack of atomistic simulation models able to describe spontaneous nanodomain formation in sufficiently simple but biologically relevant complex membranes. Here we use atomistic simulations to consider a binary mixture of saturated dipalmitoylphosphatidylcholine and cholesterol — the “minimal standard” for nanodomain formation. The simulations reveal how cholesterol drives the formation of fluid cholesterol-rich nanodomains hosting hexagonally packed cholesterol-poor lipid nanoclusters, both of which show registration between the membrane leaflets. The complex nanodomain substructure forms when cholesterol positions itself in the domain boundary region. Here cholesterol can also readily flip–flop across the membrane. Most importantly, replacing cholesterol with a sterol characterized by a less asymmetric ring region impairs the emergence of nanodomains. The model considered explains a plethora of controversial experimental results and provides an excellent basis for further computational studies on nanodomains. Furthermore, the results highlight the role of cholesterol as a key player in the modulation of nanodomains for membrane protein function.

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Section: Discussionsupporting

confidence: 78%

Nanoscale Membrane Domain Formation Driven by Cholesterol

Javanainen

Martinez‐Seara

Vattulainen

2017

Sci Rep

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“…Cholesterol is also required to maintain the signaling capacity of lipid rafts (see Simons and Toomre, 2000; Fielding and Fielding, 2004; Grouleff et al, 2015). Sengupta has shown (2012) that cholesterol modulates the depth as well as the orientation of caveolin-1 binding to membranes and that cholesterol stabilizes the more open conformations of caveolin-1.…”

Section: Discussionmentioning

confidence: 99%

“…Cholesterol appears to be involved in a variety of physiological functions in addition to regulating ion channels and membrane dynamics. Cholesterol may serve both as a steroid hormone precursor in mitochondria (Clark and Stocco, 1996; Miller and Strauss, 1999) as well as structural elements of ion channels and as control elements (Simons and Toomre, 2000; Fielding and Fielding, 2004; Grouleff et al, 2015) in multiple response systems.…”

Section: Discussionmentioning

confidence: 99%

Molecular Properties of Globin Channels and Pores: Role of Cholesterol in Ligand Binding and Movement

Morrill

Kostellow

2016

Front. Physiol.

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Globins contain one or more cavities that control or affect such functions as ligand movement and ligand binding. Here we report that the extended globin family [cytoglobin (Cygb); neuroglobin (Ngb); myoglobin (Mb); hemoglobin (Hb) subunits Hba(α); and Hbb(β)] contain either a transmembrane (TM) helix or pore-lining region as well as internal cavities. Protein motif/domain analyses indicate that Ngb and Hbb each contain 5 cholesterol- binding (CRAC/CARC) domains and 1 caveolin binding motif, whereas the Cygb dimer has 6 cholesterol-binding domains but lacks caveolin-binding motifs. Mb and Hba each exhibit 2 cholesterol-binding domains and also lack caveolin-binding motifs. The Hb αβ-tetramer contains 14 cholesterol-binding domains. Computer algorithms indicate that Cygb and Ngb cavities display multiple partitions and C-terminal pore-lining regions, whereas Mb has three major cavities plus a C-terminal pore-lining region. The Hb tetramer exhibits a large internal cavity but the subunits differ in that they contain a C-terminal TM helix (Hba) and pore-lining region (Hbb). The cavities include 43 of 190 Cygb residues, 38 of 151 of Ngb residues, 55 of 154 Mb residues, and 137 of 688 residues in the Hb tetramer. Each cavity complex includes 6 to 8 residues of the TM helix or pore-lining region and CRAC/CARC domains exist within all cavities. Erythrocyte Hb αβ-tetramers are largely cytosolic but also bind to a membrane anion exchange protein, “band 3,” which contains a large internal cavity and 12 TM helices (5 being pore-lining regions). The Hba TM helix may be the erythrocyte membrane “band 3” attachment site. “Band 3” contributes 4 caveolin binding motifs and 10 CRAC/CARC domains. Cholesterol binding may create lipid-disordered phases that alter globin cavities and facilitate ligand movement, permitting ion channel formation and conformational changes that orchestrate anion and ligand (O2, CO2, NO) movement within the large internal cavities and channels of the globins.

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“… suggested that the fluidity of a membrane decreases with an increase in PA content, due to the very small headgroup of PA that leads to the lateral condensation of the lipid tails. Some lipids, such as cholesterol, are known to reduce membrane fluidity , and due to such influence, cholesterol indirectly modulates the function of some membrane proteins , such as cholecystokinin receptor or GABA receptor . But, due to the low content of PA in membranes, the putative ability of PA to affect membrane fluidity should not influence the properties of membrane proteins noticeably.…”

Section: Chemical Properties Of Pamentioning

confidence: 99%

Phosphatidic acid in membrane rearrangements

et al. 2019

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Phosphatidic acid (PA) is the simplest cellular glycerophospholipid characterized by unique biophysical properties: a small headgroup; negative charge; and a phosphomonoester group. Upon interaction with lysine or arginine, PA charge increases from −1 to −2 and this change stabilizes protein–lipid interactions. The biochemical properties of PA also allow interactions with lipids in several subcellular compartments. Based on this feature, PA is involved in the regulation and amplification of many cellular signalling pathways and functions, as well as in membrane rearrangements. Thereby, PA can influence membrane fusion and fission through four main mechanisms: it is a substrate for enzymes producing lipids (lysophosphatidic acid and diacylglycerol) that are involved in fission or fusion; it contributes to membrane rearrangements by generating negative membrane curvature; it interacts with proteins required for membrane fusion and fission; and it activates enzymes whose products are involved in membrane rearrangements. Here, we discuss the biophysical properties of PA in the context of the above four roles of PA in membrane fusion and fission.

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The influence of cholesterol on membrane protein structure, function, and dynamics studied by molecular dynamics simulations

Cited by 159 publications

References 138 publications

Nanoscale Membrane Domain Formation Driven by Cholesterol

Nanoscale Membrane Domain Formation Driven by Cholesterol

Molecular Properties of Globin Channels and Pores: Role of Cholesterol in Ligand Binding and Movement

Phosphatidic acid in membrane rearrangements

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