Cholesterol stabilizes fluid phosphoinositide domains

Jiang, Zhiping; Redfern, Roberta E.; Isler, Yasmin; Ross, Alonzo H.; Gericke, Arne

doi:10.1016/j.chemphyslip.2014.02.003

Cited by 47 publications

(68 citation statements)

References 47 publications

(75 reference statements)

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“…One important feature could be a prearrangement of lipid species into domains that in turn could affect AnxA2 binding. Such preformed domains, in particular a cholesterol-dependent clustering of PI(4,5)P 2 , have indeed been observed in model membranes containing 20 mol % porcine brain PI(4,5)P 2 (75)(76)(77). However, our bilayer composition containing 3% PI(4,5)P 2 with two unsaturated acyl chains showed no tendency of forming micrometer-sized lipid domains, at least when analyzed in GUVs using labeled PI(4,5)P 2 (13).…”

Section: Discussionmentioning

confidence: 82%

Cooperative Binding of Annexin A2 to Cholesterol- and Phosphatidylinositol-4,5-Bisphosphate-Containing Bilayers

Drücker¹,

Pejic²,

Grill³

et al. 2014

Biophysical Journal

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Biological membranes are organized into dynamic microdomains that serve as sites for signal transduction and membrane trafficking. The formation and expansion of these microdomains are driven by intrinsic properties of membrane lipids and integral as well as membrane-associated proteins. Annexin A2 (AnxA2) is a peripherally associated membrane protein that can support microdomain formation in a Ca(2+)-dependent manner and has been implicated in membrane transport processes. Here, we performed a quantitative analysis of the binding of AnxA2 to solid supported membranes containing the annexin binding lipids phosphatidylinositol-4,5-bisphosphate and phosphatidylserine in different compositions. We show that the binding is of high specificity and affinity with dissociation constants ranging between 22.1 and 32.2 nM. We also analyzed binding parameters of a heterotetrameric complex of AnxA2 with its S100A10 protein ligand and show that this complex has a higher affinity for the same membranes with Kd values of 12 to 16.4 nM. Interestingly, binding of the monomeric AnxA2 and the AnxA2-S100A10 complex are characterized by positive cooperativity. This cooperative binding is mediated by the conserved C-terminal annexin core domain of the protein and requires the presence of cholesterol. Together our results reveal for the first time, to our knowledge, that AnxA2 and its derivatives bind cooperatively to membranes containing cholesterol, phosphatidylserine, and/or phosphatidylinositol-4,5-bisphosphate, thus providing a mechanistic model for the lipid clustering activity of AnxA2.

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Section: Discussionmentioning

confidence: 82%

Cooperative Binding of Annexin A2 to Cholesterol- and Phosphatidylinositol-4,5-Bisphosphate-Containing Bilayers

Drücker¹,

Pejic²,

Grill³

et al. 2014

Biophysical Journal

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“…Moreover, recent MD simulations suggested that MA may induce lateral segregation of PI(4,5)P 2 into domains which may by itself promote efficient MA binding, for example through locally enhanced electrostatic interactions (78). There is also experimental evidence that cholesterol helps stabilize PI(4,5)P 2 in lipid clusters (79), which rationalizes that cholesterol and PI(4,5)P 2 synergistically attract MA to the membrane, as shown in Fig. 4 and 5.…”

Section: Discussionmentioning

confidence: 99%

Membrane Binding of HIV-1 Matrix Protein: Dependence on Bilayer Composition and Protein Lipidation

Barros

Heinrich

Datta

et al. 2016

J Virol

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By assembling in a protein lattice on the host's plasma membrane, the retroviral Gag polyprotein triggers formation of the viral protein/membrane shell. The MA domain of Gag employs multiple signals-electrostatic, hydrophobic, and lipid-specific-to bring the protein to the plasma membrane, thereby complementing protein-protein interactions, located in full-length Gag, in lattice formation. We report the interaction of myristoylated and unmyristoylated HIV-1 Gag MA domains with bilayers composed of purified lipid components to dissect these complex membrane signals and quantify their contributions to the overall interaction. Surface plasmon resonance on well-defined planar membrane models is used to quantify binding affinities and amounts of protein and yields free binding energy contributions, ⌬G, of the various signals. Charge-charge interactions in the absence of the phosphatidylinositide PI(4,5)P 2 attract the protein to acidic membrane surfaces, and myristoylation increases the affinity by a factor of 10; thus, our data do not provide evidence for a PI(4,5)P 2 trigger of myristate exposure. Lipid-specific interactions with PI(4,5)P 2 , the major signal lipid in the inner plasma membrane, increase membrane attraction at a level similar to that of protein lipidation. While cholesterol does not directly engage in interactions, it augments protein affinity strongly by facilitating efficient myristate insertion and PI(4,5)P 2 binding. We thus observe that the isolated MA protein, in the absence of protein-protein interaction conferred by the full-length Gag, binds the membrane with submicromolar affinities. IMPORTANCELike other retroviral species, the Gag polyprotein of HIV-1 contains three major domains: the N-terminal, myristoylated MA domain that targets the protein to the plasma membrane of the host; a central capsid-forming domain; and the C-terminal, genome-binding nucleocapsid domain. These domains act in concert to condense Gag into a membrane-bounded protein lattice that recruits genomic RNA into the virus and forms the shell of a budding immature viral capsid. In binding studies of HIV-1 Gag MA to model membranes with well-controlled lipid composition, we dissect the multiple interactions of the MA domain with its target membrane. This results in a detailed understanding of the thermodynamic aspects that determine membrane association, preferential lipid recruitment to the viral shell, and those aspects of Gag assembly into the membrane-bound protein lattice that are determined by MA. T he polyprotein Gag is an essential component for the reproduction of retroviruses, such as HIV-1, in infected cells. In the production of new viruses, many copies of Gag assemble laterally, either in the cytoplasm or on the plasma membrane (PM) of the host, thus acquiring their lipid envelope as they bud from the cell. Distinct retroviral genera encode Gag proteins which all show a similar domain architecture, with an N-terminal matrix (MA) domain that targets the PM, followed by the capsid (CA) and nucleocapsid ...

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“…Phosphoinositides are also commercially available with di-oleoyl (DOPIPs) or di-palmitoyl acyl (di-C 16 PIPs) chains. DOPIPs will form fluid phases, however, the phase behavior in the presence of other membrane components like cholesterol deviates slightly from what is observed for SAPIPs [17]. DPPIPs form ordered (gel) phases at room temperature [18], resulting in a reduced mobility and lateral spacing of di-C 16 PIPs in comparison to SAPIPs and even though PTEN penetrates the bilayer only to a limited extent [19, 20], bilayer model systems involving saturated chain phosphoinositides are less suitable to study PTEN membrane association.…”

Section: Biomembrane Mimics For the Characterization Of Membrane-amentioning

confidence: 99%

Biophysical methods for the characterization of PTEN/lipid bilayer interactions

Harishchandra

Neumann

Gericke

et al. 2015

Methods

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PTEN, a tumor suppressor protein that dephosphorylates phosphoinositides at the 3-position of the inositol ring, is a cytosolic protein that needs to associate with the plasma membrane or other subcellular membranes to exert its lipid phosphatase function. Upon membrane association PTEN interacts with at least three different lipid entities: An anionic lipid that is present in sufficiently high concentration to create a negative potential that allows PTEN to interact electrostatically with the membrane, phosphatidylinositol-4,5-bisphosphate, which interacts with PTEN's N-terminal end and the substrate, usually phosphatidylinositol-3,4,5-trisphosphate. Many parameters influence PTEN's interaction with the lipid bilayer, for example, the lateral organization of the lipids or the presence of other chemical species like cholesterol or other lipids. To investigate systematically the different steps of PTEN's complex binding mechanism and to explore its dynamic behavior in the membrane bound state, in vitro methods need to be employed that allow for a systematic variation of the experimental conditions. In this review we survey a variety of methods that can be used to assess PTEN lipid binding affinity, the dynamics of its membrane association as well as its dynamic behavior in the membrane bound state.

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Cholesterol stabilizes fluid phosphoinositide domains

Cited by 47 publications

References 47 publications

Cooperative Binding of Annexin A2 to Cholesterol- and Phosphatidylinositol-4,5-Bisphosphate-Containing Bilayers

Cooperative Binding of Annexin A2 to Cholesterol- and Phosphatidylinositol-4,5-Bisphosphate-Containing Bilayers

Membrane Binding of HIV-1 Matrix Protein: Dependence on Bilayer Composition and Protein Lipidation

Biophysical methods for the characterization of PTEN/lipid bilayer interactions

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