Identification of Specific Lipid-binding Sites in Integral Membrane Proteins

Lensink, Marc F.; Govaerts, Cédric; Ruysschaert, Jean‐Marie

doi:10.1074/jbc.m109.068890

Cited by 33 publications

(37 citation statements)

References 64 publications

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“…A primary aim of this study was to determine the molecular basis for the ability of the foreign lipid PC to support native topological organization and downhill transport (9) but not uphill transport (9)(10)(11) or the structure of domain P7 of E. coli LacY (8). The differences between PE and PC in supporting function of several secondary transport proteins has focused on the mode of direct interaction between the lipid head groups and specific amino acids of the mature protein during catalysis (12,13,16,28), which, based on our results, appears not to be the case. Our results suggest that the major effect of the lipid environment occurs during folding of the protein into its final structure (i.e., P7 conformation) rather than specific lipid-protein interactions after native structure is attained.…”

Section: Discussionmentioning

confidence: 40%

Plasticity of lipid-protein interactions in the function and topogenesis of the membrane protein lactose permease from Escherichia coli

Bogdanov¹,

Heacock²,

Guan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

115

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Phosphatidylcholine (PC) has been widely used in place of naturally occurring phosphatidylethanolamine (PE) in reconstitution of bacterial membrane proteins. However, PC does not support native structure or function for several reconstituted transport proteins. Lactose permease (LacY) of Escherichia coli, when reconstituted in E. coli phospholipids, exhibits energy-dependent uphill and energy-independent downhill transport function and proper conformation of periplasmic domain P7, which is tightly linked to uphill transport function. LacY expressed in cells lacking PE and containing only anionic phospholipids exhibits only downhill transport and lacks native P7 conformation. Reconstitution of LacY in the presence of E. coli-derived PE, but not dioleoyl-PC, results in uphill transport. We now show that LacY exhibits uphill transport and native conformation of P7 when expressed in a mutant of E. coli in which PC completely replaces PE even though the structure is not completely native. E. coli-derived PC and synthetic PC species containing at least one saturated fatty acid also support the native conformation of P7 dependent on the presence of anionic phospholipids. Our results demonstrate that the different effects of PE and PC species on LacY structure and function cannot be explained by differences in the direct interaction of the lipid head groups with specific amino acid residues alone but are due to more complex effects of the physical and chemical properties of the lipid environment on protein structure. This conclusion is supported by the effect of different lipids on the proper folding of domain P7, which indirectly influences uphill transport function.

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Section: Discussionmentioning

confidence: 40%

Plasticity of lipid-protein interactions in the function and topogenesis of the membrane protein lactose permease from Escherichia coli

Bogdanov¹,

Heacock²,

Guan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

115

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“…Asp68 is directly involved in protein-lipid interaction, as also highlighted by the simulations of LacY in PE (Lensink et al, 2010).…”

Section: Lmrpmentioning

confidence: 95%

“…Additional studies on a range of other transporters (Zhang et al, 2003(Zhang et al, , 2005Vitrac et al, 2011) showed that PE-dependent topological misorientation depends on the presence of negatively charged residues on the protein surface. Under physiological membrane conditions, positively charged residues bias the protein domain to insert in such a way that these residues face the cytoplasm, an effect known as the "positive-inside rule" (von Heijne, 1986,Figure 3: A tight coupling between a POPE lipid and the LacY transporter was predicted by MD simulations (Lensink et al, 2010). The PE headgroup forms salt-bridges to Asp68 and Lys69, which are part of a highly conserved motif in MFS transporters (Griffith et al, 1992).…”

Section: Lacymentioning

confidence: 99%

“…PS and mono-and di-methylated PE could substitute for PE (Chen and Wilson, 1984;Wang et al, 2002), indicating that interactions between the protein and the amine of the headgroup might be important. Molecular dynamics simulations of LacY in a PE membrane identified a specific salt-bridge between a PE lipid headgroup and the charged residues Asp68 and Lys69 in LacY (Lensink et al, 2010) (Fig. 3).…”

Section: Lacymentioning

confidence: 99%

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Influence of lipids on protein-mediated transmembrane transport

Denning

Beckstein

2013

Chemistry and Physics of Lipids

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Transmembrane proteins are responsible for transporting ions and small molecules across the hydrophobic region of the cell membrane. We are reviewing the evidence for regulation of these transport processes by interactions with the lipids of the membrane. We focus on ion channels, including potassium channels, mechanosensitive and pentameric ligand gated ion channels, and active transporters, including pumps, sodium or proton driven secondary transporters and ABC transporters. For ion channels it has been convincingly shown that specific lipid-protein interactions can directly affect their function. In some cases, a combined approach of molecular and structural biology together with computer simulations has revealed the molecular mechanisms. There are also many transporters whose activity depends on lipids but understanding of the molecular mechanisms is only beginning.

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“…It has also been demonstrated to be compatible with AMBER99SB and could give marginally better free energy calculations than the widely used OPLS/Berger combination [31]. While simulations of membrane proteins using such hybrid parameters have been validated by various groups [32][33][34], the combination of different force fields require care. Protein lipid interactions in Berger-OPLS and Berger-GROMOS have been found to be overestimated and result in drastic changes of lipid properties upon protein insertion [13,27].…”

Section: United-atom (Ua) Lipid Models: the Best Of Both Worlds?mentioning

confidence: 99%

Bioinformatics for Membrane Lipid Simulations: Models, Computational Methods, and Web Server Tools

Leong¹,

Lim²,

Choong³

2016

Bioinformatics - Updated Features and Applications

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Biological membranes are complex environments consisting of different types of lipids and membrane proteins. The structure of a lipid bilayer is typically difficult to study because the membrane liquid crystalline state is made up of multiple disordered lipid molecules. This complicates the description of the lipid membrane properties by the conformation of any single lipid molecule. Molecular dynamics (MD) simulations have been used extensively to investigate properties of membrane lipids, lipid vesicles, and membrane protein systems. All-atom membrane models can elucidate detailed contacts between membrane proteins and its surrounding lipids, while united-atom and coarsegrained description have allowed larger models and longer timescales up to microsecond mark to be probed. Additionally, membrane models with mixed phospholipids and lipopolysaccharide content have made it possible to model improved views of biological membranes. Here, we present an overview of commonly used lipid force fields by the biosimulation community, useful tools for membrane MD simulations, and recent advances in membrane simulations.

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Identification of Specific Lipid-binding Sites in Integral Membrane Proteins

Cited by 33 publications

References 64 publications

Plasticity of lipid-protein interactions in the function and topogenesis of the membrane protein lactose permease from Escherichia coli

Plasticity of lipid-protein interactions in the function and topogenesis of the membrane protein lactose permease from Escherichia coli

Influence of lipids on protein-mediated transmembrane transport

Bioinformatics for Membrane Lipid Simulations: Models, Computational Methods, and Web Server Tools

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