Chemical control of phospholipid distribution across bilayer membranes

Boon, J. Middleton; Smith, Bradley D.

doi:10.1002/med.10009

Cited by 213 publications

(180 citation statements)

References 237 publications

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“…Alternatively, a more direct role of SLs in protecting Gap1 against ubiquitination could also be considered. Although mammalian SLs are known to reside mainly in the exoplasmic leaflet of the plasma membrane (Holthuis et al, 2001), ϳ20% of them are found in the cytoplasmic leaflet (Boon and Smith, 2002). Even if no data are currently available about the distribution of SLs over the two leaflets of the yeast plasma membrane (van Meer and Holthuis, 2000), it is thus conceivable that at least a small fraction of these lipids face the cytoplasm, in particular if they are forming a shell around transmembrane proteins.…”

Section: Discussionmentioning

confidence: 99%

Evidence for Coupled Biogenesis of Yeast Gap1 Permease and Sphingolipids: Essential Role in Transport Activity and Normal Control by Ubiquitination

Lauwers

Großmann

André

2007

MBoC

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Current models for plasma membrane organization integrate the emerging concepts that membrane proteins tightly associate with surrounding lipids and that biogenesis of surface proteins and lipids may be coupled. We show here that the yeast general amino acid permease Gap1 synthesized in the absence of sphingolipid (SL) biosynthesis is delivered to the cell surface but undergoes rapid and unregulated down-regulation. Furthermore, the permease produced under these conditions but blocked at the cell surface is inactive, soluble in detergent, and more sensitive to proteases. We also show that SL biogenesis is crucial during Gap1 production and secretion but that it is dispensable once Gap1 has reached the plasma membrane. Moreover, the defects displayed by cell surface Gap1 neosynthesized in the absence of SL biosynthesis are not compensated by subsequent restoration of SL production. Finally, we show that down-regulation of Gap1 caused by lack of SL biogenesis involves the ubiquitination of the protein on lysines normally not accessible to ubiquitination and close to the membrane. We propose that coupled biogenesis of Gap1 and SLs would create an SL microenvironment essential to the normal conformation, function, and control of ubiquitination of the permease. INTRODUCTIONBiological membranes were long seen as a "fluid mosaic" of proteins simply dispersed in a homogeneous lipid bilayer (Singer and Nicholson, 1972). This view contrasts with current models of the plasma membrane that take into account the heterogeneity of lipids in length and structure and the very high density of intrinsic proteins, ϳ30,000 per m 2 (Jacobson et al., 2007). These models also integrate the important notion of lateral heterogeneity, i.e., that the plasma membrane contains domains of various lipid compositions and physical properties. Among these domains, lipid rafts have been the subject of many studies. Although the definition of rafts is still debated (Pike, 2006), they are generally viewed as small domains of various sizes (ϳ10 -200 nm in diameter) that are formed by the dynamic assembly of sphingolipids with sterols (Simons and Ikonen, 1997;Jacobson et al., 2007). These domains selectively include or exclude proteins, and they are thought to exist in a liquid-ordered phase distinct from the bulk liquid-disordered phase of the membrane (Brown and London, 1998). Their tightly packed state makes them more resistant to solubilization by nonionic detergents such as Triton X-100, so that they yield detergent-resistant membranes (DRMs) after detergent extraction in the cold (London and Brown, 2000). Despite the limitations of detergent-dependent methods and the caution that must be exerted when interpreting the resulting data, the isolation of DRMs remains a useful tool for investigating protein-lipid interactions and membrane domains (Brown and London, 1998;Shogomori and Brown, 2003;Lichtenberg et al., 2005). A complementary approach consists in visualizing raft components directly in the plasma membrane of living cells. In Saccharomyces ...

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Section: Discussionmentioning

confidence: 99%

Evidence for Coupled Biogenesis of Yeast Gap1 Permease and Sphingolipids: Essential Role in Transport Activity and Normal Control by Ubiquitination

Lauwers

Großmann

André

2007

MBoC

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“…Asymmetric lipid distributions between the inner and outer bilayer leaflets (35)(36)(37) were further considered to specifically model the composition of the inner leaflet of the plasma membrane (Table 1). To simulate the composition of a lipid raft (38 -41), we mixed sphingomyelin and cholesterol with zwitterionic PE and anionic PS ( Table 1).…”

Section: Methodsmentioning

confidence: 99%

Lipid Rafts Alter the Stability and Activity of the Cholera Toxin A1 Subunit

Ray

Taylor

Banerjee

et al. 2012

Journal of Biological Chemistry

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“…Yet the understanding of the molecular mechanisms of lipid flip-flops is of substantial biological importance since a loss of transmembrane lipid asymmetry can have severe consequences. 10 For instance, while negatively charged phosphatidylserine lipids are usually located in the inner leaflet of the plasma membrane, their appearance in the outer leaflet is known to correlate with programmed cell death. 5 In more general terms, understanding how membrane lipids maintain the asymmetric transmembrane distribution and achieve their nonrandom distribution in cells is one of the key challenges in cell biology.…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanism for Lipid Flip-Flops

2007

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Transmembrane lipid translocation (flip-flop) processes are involved in a variety of properties and functions of cell membranes, such as membrane asymmetry and programmed cell death. Yet, flip-flops are one of the least understood dynamical processes in membranes. In this work, we elucidate the molecular mechanism of pore-mediated transmembrane lipid translocation (flip-flop) acquired from extensive atomistic molecular dynamics simulations. On the basis of 50 successful flip-flop events resolved in atomic detail, we demonstrate that lipid flip-flops may spontaneously occur in protein-free phospholipid membranes under physiological conditions through transient water pores on a time scale of tens of nanoseconds. While the formation of a water pore is induced here by a transmembrane ion density gradient, the particular way by which the pore is formed is irrelevant for the reported flip-flop mechanism: the appearance of a transient pore (defect) in the membrane inevitably leads to diffusiVe translocation of lipids through the pore, which is driven by thermal fluctuations. Our findings strongly support the idea that the formation of membrane defects in terms of water pores is the rate-limiting step in the process of transmembrane lipid flip-flop, which, on average, requires several hours. The findings are consistent with available experimental and computational data and provide a view to interpret experimental observations. For example, the simulation results provide a molecular-level explanation in terms of pores for the experimentally observed fact that the exposure of lipid membranes to electric field pulses considerably reduces the time required for lipid flip-flops.

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Chemical control of phospholipid distribution across bilayer membranes

Cited by 213 publications

References 237 publications

Evidence for Coupled Biogenesis of Yeast Gap1 Permease and Sphingolipids: Essential Role in Transport Activity and Normal Control by Ubiquitination

Evidence for Coupled Biogenesis of Yeast Gap1 Permease and Sphingolipids: Essential Role in Transport Activity and Normal Control by Ubiquitination

Lipid Rafts Alter the Stability and Activity of the Cholera Toxin A1 Subunit

Molecular Mechanism for Lipid Flip-Flops

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