Emerging Diversity in Lipid–Protein Interactions

Corradi, Valentina; Sejdiu, Besian I.; Mesa-Galloso, Haydeé; Abdizadeh, Haleh; Noskov, Sergei Y.; Marrink, Siewert J.; Tieleman, D. Peter

doi:10.1021/acs.chemrev.8b00451

Cited by 332 publications

(365 citation statements)

References 864 publications

(1,926 reference statements)

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“…It is well established that the constituents of the membrane can influence protein function and cellular processes through nonspecific physical properties (Her et al, 2016;Morigaki & Tanimoto, 2018;Shaw, McLean, & Sligar, 2004), but the details of these effects remain unresolved. Similarly, specific interactions between lipids, including cholesterol with binding sites on proteins, contribute to the overall energetics of the folded protein and functionally relevant conformational changes (Corradi et al, 2019;Fantini & Barrantes, 2013;Fantini, Epand, & Barrantes, 2019;Kimura, Jennings, & Epand, 2016). As our appreciation for the complexity and sophistication of membrane-protein interactions increases, it is likely that interest in nanodiscs with greater complexity and sophistication will increase in parallel.…”

Section: Introductionmentioning

confidence: 99%

Preparation of Lipid Nanodiscs with Lipid Mixtures

Atkins

McClary

2019

CP Protein Science

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Lipid nanodiscs provide a native‐like lipid environment for membrane proteins, and they have become a valuable platform for the study of membrane biophysics. A range of biophysical and biochemical analyses are enabled when membrane proteins are captured in lipid nanodiscs. Two parameters that can be controlled when capturing membrane proteins in lipid nanodiscs are the radius, and hence the surface area of the lipid surface, and the composition of the lipid bilayer. Despite their emergence as a versatile tool, most studies with lipid nanodiscs in the literature have focused on nanodiscs of a single radius with a single lipid. In light of the complexity of biological membranes, it is likely that nanodiscs with multiple membrane components would be more sophisticated models for membrane research. It is possible to prepare nanodiscs with more complex lipid mixtures to probe the effects of lipid composition on several aspects of membrane biochemistry. Detailed protocols are described here for the preparation of nanodiscs with mixtures of phospholipids, incorporation of cholesterol, and incorporation of a spectroscopic lipid probe. These protocols provide starting points for the construction of nanodiscs with more physiological membrane compositions or with useful biophysical probes. © 2019 by John Wiley & Sons, Inc. Basic Protocol 1: Assembly of mixed lipid nanodiscs Basic Protocol 2: Assembly of nanodiscs with cholesterol Basic Protocol 3: Incorporation of laurdan into nanodiscs for membrane fluidity measurements

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Section: Introductionmentioning

confidence: 99%

Preparation of Lipid Nanodiscs with Lipid Mixtures

Atkins

McClary

2019

CP Protein Science

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“…Molecular dynamics (MD) simulations enable exploration of how the physical properties of a membrane (19) and/or direct lipid interactions (20,21) may alter the conformational dynamics of membrane proteins (15,22). For example, a crystal structure of the Class A GPCR β2-adrenegic receptor identified cholesterol bound to the intracellular region of TM4 (23), which was validated by observation of cholesterol binding to the same binding site in MD simulations (24).…”

Section: Introductionmentioning

confidence: 99%

The Glycosphingolipid GM3 Modulates Conformational Dynamics of the Glucagon Receptor

Ansell

Song

Sansom

2020

Preprint

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The extracellular domain (ECD) of Class B1 G-protein coupled receptors (GPCRs) plays a central role in signal transduction and is uniquely positioned to sense both the extracellular and membrane environments. Whilst recent studies suggest a role for membrane lipids in the modulation of Class A and Class F GPCR signalling properties, little is known about the effect of lipids on Class B1 receptors. In this study, we employed multiscale molecular dynamics (MD) simulations to access the dynamics of the glucagon receptor (GCGR) ECD in the presence of native-like membrane bilayers.Simulations showed that the ECD could move about a hinge region formed by residues Q122-E126 to adopt both closed and open conformations relative to the TMD. ECD movements were modulated by binding of the glycosphingolipid GM3. These large-scale fluctuations in ECD conformation that may affect the ligand binding and receptor activation properties. We also identify a unique PIP2 interaction profile near ICL2/TM3 at the G-protein coupling interface, suggesting a mechanism of engaging G-proteins which may have a distinct dependence on PIP2 compared to Class A GPCRs.Given the structural conservation of Class B1 GPCRs, the modulatory effects of GM3 and PIP2 on GCGR may be conserved across these receptors, offering new insights into potential therapeutic targeting. Statement of SignificanceThe role of lipids in regulation of Class B GPCRs remains elusive, despite recent structural advances. In this study, multi-scale molecular dynamics simulations are used to evaluate lipid interactions with the glucagon receptor, a Class B1 GPCR. We find that the glycosphingolipid GM3 binds to the glucagon receptor extracellular domain (ECD), modulating the dynamics of the ECD and promoting movement away from the transmembrane domain . We also identify a unique PIP2 interaction fingerprint in a region known to be important for bridging G-protein coupling in Class A GPCRs. Thus, this study provides molecular insight into the behaviour of the glucagon receptor in a complex lipid bilayer environment which may aid understanding of glucagon receptor signalling properties.GCGR_main text v16 figs MS biorxiv.docx

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“…Interlipid interactions in membranes occur in a stereoselective manner and induce the formation of the lipid phase and domains with various sizes ranging from tens of micrometers to single‐digit nanometers in model membranes. Some membrane proteins are known to specifically interact with chiral ligand lipids, and concurrent interactions with the surrounding lipids lead to the regulation of functions and localization of proteins . Chiral centers of GPLs and SM reside around the membrane water‐lipid interface of planar bilayers.…”

Section: Introductionmentioning

confidence: 99%

“…Some membrane proteins are known to specifically interact with chiral ligand lipids, and concurrent interactions with the surrounding lipids lead to the regulation of functions and localization of proteins. 6 Chiral centers of GPLs and SM reside around the membrane water-lipid interface of planar bilayers. Therefore, such lipid chirality can be involved in various membrane events via the determination of the orientations of acyl chains and the head group, as well as in membrane hydration.…”

mentioning

confidence: 99%

Enantiomers of phospholipids and cholesterol: A key to decipher lipid‐lipid interplay in membrane

2020

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Most phospholipids constituting biological membranes are chiral molecules with a hydrophilic head group and hydrophobic alkyl chains, rendering biphasic property characteristic of membrane lipids. Some lipids assemble into small domains via chirality‐dependent homophilic and heterophilic interactions, the latter of which sometimes include cholesterol to form lipid rafts and other microdomains. On the other hand, lipid mediators and hormones derived from chiral lipids are recognized by specific membrane or nuclear receptors to induce downstream signaling. It is crucial to clarify the physicochemical properties of the lipid self‐assembly for the study of the functions and behavior of biological membranes, which often become elusive due to effects of membrane proteins and other biological events. Three major lipids with different skeletal structures were discussed: sphingolipids including ceramides, phosphoglycerolipids, and cholesterol. The physicochemical properties of membranes and physiological functions of lipid enantiomers and diastereomers were described in comparison to natural lipids. When each enantiomer formed a self‐assembly or interacted with achiral lipids, both lipid enantiomers exhibited identical membrane physicochemical properties, while when the enantiomer interacted with chiral lipids or with the opposite enantiomer, mixed membranes exhibited different properties. For example, racemic membranes comprising native sphingomyelin and its antipode exhibited phase segregation due to their strong homophilic interactions. Therefore, lipid enantiomers and diastereomers can be good probes to investigate stereospecific lipid‐lipid and lipid‐protein interactions occurring in biological membranes.

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Emerging Diversity in Lipid–Protein Interactions

Cited by 332 publications

References 864 publications

Preparation of Lipid Nanodiscs with Lipid Mixtures

Preparation of Lipid Nanodiscs with Lipid Mixtures

The Glycosphingolipid GM3 Modulates Conformational Dynamics of the Glucagon Receptor

Enantiomers of phospholipids and cholesterol: A key to decipher lipid‐lipid interplay in membrane

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