Assessing the Role of Lipids in the Molecular Mechanism of Membrane Proteins

Jodaitis, Léni; Oene, Thomas van; Martens, Chloé

doi:10.3390/ijms22147267

Cited by 10 publications

(11 citation statements)

References 153 publications

(183 reference statements)

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“…As we are confident of our activity assay, we sought out a less trivial explanation of this discrepancy. In view of the growing body of evidence for the importance of lipids in the mechanisms of membrane proteins, including allostery [ 34 ], we measured the substrate saturation profile for DDM-solubilized Dh-mPPase and compared it with the profile for the IMV-bound enzyme (the uppermost curves in Figure 3 and Figure 5 ). This comparison demonstrated the close similarity of the two profiles ( Figure S3 ) and the parameters derived therefrom ( Table S2 ).…”

Section: Resultsmentioning

confidence: 99%

Catalytic Asymmetry in Homodimeric H+-Pumping Membrane Pyrophosphatase Demonstrated by Non-Hydrolyzable Pyrophosphate Analogs

Anashkin

Malinen

Bogachev

et al. 2021

IJMS

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Membrane-bound inorganic pyrophosphatase (mPPase) resembles the F-ATPase in catalyzing polyphosphate-energized H+ and Na+ transport across lipid membranes, but differs structurally and mechanistically. Homodimeric mPPase likely uses a “direct coupling” mechanism, in which the proton generated from the water nucleophile at the entrance to the ion conductance channel is transported across the membrane or triggers Na+ transport. The structural aspects of this mechanism, including subunit cooperation, are still poorly understood. Using a refined enzyme assay, we examined the inhibition of K+-dependent H+-transporting mPPase from Desulfitobacterium hafniensee by three non-hydrolyzable PPi analogs (imidodiphosphate and C-substituted bisphosphonates). The kinetic data demonstrated negative cooperativity in inhibitor binding to two active sites, and reduced active site performance when the inhibitor or substrate occupied the other active site. The nonequivalence of active sites in PPi hydrolysis in terms of the Michaelis constant vanished at a low (0.1 mM) concentration of Mg2+ (essential cofactor). The replacement of K+, the second metal cofactor, by Na+ increased the substrate and inhibitor binding cooperativity. The detergent-solubilized form of mPPase exhibited similar active site nonequivalence in PPi hydrolysis. Our findings support the notion that the mPPase mechanism combines Mitchell’s direct coupling with conformational coupling to catalyze cation transport across the membrane.

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Section: Resultsmentioning

confidence: 99%

Catalytic Asymmetry in Homodimeric H+-Pumping Membrane Pyrophosphatase Demonstrated by Non-Hydrolyzable Pyrophosphate Analogs

Anashkin

Malinen

Bogachev

et al. 2021

IJMS

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“…Experimental studies have also been carried out that provide evidence of the activation of transmembrane proteins as a result of alterations to the lipid composition, e.g., using the mild detergent Triton X-100 [541,542], the relationship between lateral pressure profile and lipid composition was investigated both experimentally [697] and through MD simulation [698]. A few MD simulation studies found specific effects due to direct lipid interaction on protein behavior e.g., [699][700][701][702][703][704][705]; in most cases, the cholesterol molecules in the membrane were, however, most frequently shown to play the role of modulating the behavior of membrane proteins [706][707][708][709][710].…”

Section: Drug Membrane Interaction Can Play a Role In The Mechanism Of Drug Action-case Of Anestheticsmentioning

confidence: 99%

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021

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We review the use of molecular dynamics (MD) simulation as a drug design tool in the context of the role that the lipid membrane can play in drug action, i.e., the interaction between candidate drug molecules and lipid membranes. In the standard “lock and key” paradigm, only the interaction between the drug and a specific active site of a specific protein is considered; the environment in which the drug acts is, from a biophysical perspective, far more complex than this. The possible mechanisms though which a drug can be designed to tinker with physiological processes are significantly broader than merely fitting to a single active site of a single protein. In this paper, we focus on the role of the lipid membrane, arguably the most important element outside the proteins themselves, as a case study. We discuss work that has been carried out, using MD simulation, concerning the transfection of drugs through membranes that act as biological barriers in the path of the drugs, the behavior of drug molecules within membranes, how their collective behavior can affect the structure and properties of the membrane and, finally, the role lipid membranes, to which the vast majority of drug target proteins are associated, can play in mediating the interaction between drug and target protein. This review paper is the second in a two-part series covering MD simulation as a tool in pharmaceutical research; both are designed as pedagogical review papers aimed at both pharmaceutical scientists interested in exploring how the tool of MD simulation can be applied to their research and computational scientists interested in exploring the possibility of a pharmaceutical context for their research.

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“…Since different chemical environments will result in different 13 C chemical shift, the observed broad peak ranging from 165 to 178 ppm indicated the multiple chemical environments which the Vpr Cys-76 residue experiences. Lipid membranes have been shown to play active roles in modulating the functions of membrane associated proteins or membrane proteins [ 48 , 49 , 50 , 51 , 52 ]. Thus, the membrane cannot be viewed as a passive supporting component for the membrane protein due to the couplings between protein and membrane.…”

Section: Resultsmentioning

confidence: 99%

Cholesterol Modulates the Interaction between HIV-1 Viral Protein R and Membrane

Liu

Huang

2021

Membranes

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Being a major metabolite for maintaining cellular homeostasis, as well as an important structural component in lipid membrane, cholesterol also plays critical roles in the life cycles of some viruses, including human immunodeficiency virus-1 (HIV-1). The involvement of cholesterol in HIV-1 infectivity, assembly and budding has made it an important research target. Viral protein R (Vpr) is an accessory protein of HIV-1, which is involved in many major events in the life cycle of HIV-1. In addition to its multi-functional roles in the HIV-1 life cycle, it is shown to interact with lipid membrane and form a cation-selective channel. In this work, we examined the effect of cholesterol on the interaction of Vpr and lipid membrane. Using calcein release assay, we found that the membrane permeability induced by the membrane binding of Vpr was significantly reduced in the presence of cholesterol in membrane. In addition, using solid-state NMR (ssNMR) spectroscopy, Vpr was shown to experience multiple chemical environments in lipid membrane, as indicated by the broad line shape of carbonyl 13C resonance of Cys-76 residue ranging from 165–178 ppm, which can be attributed to the existence of complex Vpr-membrane environments. We further showed that the presence of cholesterol in membrane will alter the distribution of Vpr in the complex membrane environments, which may explain the change of the Vpr induced membrane permeability in the presence of cholesterol.

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Assessing the Role of Lipids in the Molecular Mechanism of Membrane Proteins

Cited by 10 publications

References 153 publications

Catalytic Asymmetry in Homodimeric H+-Pumping Membrane Pyrophosphatase Demonstrated by Non-Hydrolyzable Pyrophosphate Analogs

Catalytic Asymmetry in Homodimeric H+-Pumping Membrane Pyrophosphatase Demonstrated by Non-Hydrolyzable Pyrophosphate Analogs

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

Cholesterol Modulates the Interaction between HIV-1 Viral Protein R and Membrane

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