Lipid-Dependent Regulation of Ion Channels and G Protein–Coupled Receptors: Insights from Structures and Simulations

Duncan, Anna L.; Song, Wanling; Sansom, Mark S.P.

doi:10.1146/annurev-pharmtox-010919-023411

Cited by 132 publications

(123 citation statements)

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“…stably anchoring and/or promoting oligomerization an integral protein within a bilayer [1,2], or targeting a peripheral protein to the surface of a specific cellular membrane. Other interactions influence the function of the protein, either allosterically [3][4][5][6] or via a direct functional role [7,8]. The nature of these lipid interactions is, therefore, the subject of both experimental and computational analyses [6].…”

Section: Protein-lipid Interactions: Structures and Simulationsmentioning

confidence: 99%

The energetics of protein–lipid interactions as viewed by molecular simulations

Corey

Stansfeld

Sansom

2019

Biochemical Society Transactions

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Membranes are formed from a bilayer containing diverse lipid species with which membrane proteins interact. Integral, membrane proteins are embedded in this bilayer, where they interact with lipids from their surroundings, whilst peripheral membrane proteins bind to lipids at the surface of membranes. Lipid interactions can influence the function of membrane proteins, either directly or allosterically. Both experimental (structural) and computational approaches can reveal lipid binding sites on membrane proteins. It is, therefore, important to understand the free energies of these interactions. This affords a more complete view of the engagement of a particular protein with the biological membrane surrounding it. Here, we describe many computational approaches currently in use for this purpose, including recent advances using both free energy and unbiased simulation methods. In particular, we focus on interactions of integral membrane proteins with cholesterol, and with anionic lipids such as phosphatidylinositol 4,5-bis-phosphate and cardiolipin. Peripheral membrane proteins are exemplified via interactions of PH domains with phosphoinositide-containing membranes. We summarise the current state of the field and provide an outlook on likely future directions of investigation.

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Section: Protein-lipid Interactions: Structures and Simulationsmentioning

confidence: 99%

The energetics of protein–lipid interactions as viewed by molecular simulations

Corey

Stansfeld

Sansom

2019

Biochemical Society Transactions

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“…GPCR_oligo_main_text_v16 biorxiv.docx P1Y12, A2aR and β2AR and others 26 . Indeed, cholesterol was proposed to have an impact on GPCR oligomerization either via alteration of bilayer properties, e.g.…”

Section: Introductionmentioning

confidence: 99%

Modulation of A2aR Oligomerisation by Conformational State and PIP₂Interactions Revealed by MD Simulations and Markov Models

Song

Duncan

Sansom

2020

Preprint

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G protein coupled receptors (GPCRs) play key roles in cellular signalling pathways. GPCRs are suggested to form dimers and higher order oligomers in response to activation and other stimuli. However, a lack of structural details of the involvement of GPCR oligomerisation in receptor activation has held back our understanding of GPCR signalling in an in vivo context. Here, we combined extensive molecular dynamics simulations with Markov state modelling in order to understand the oligomerisation process of the Adenosine A2a receptor in response to receptor activation. The Markov state models reveal that activation leads to an increased propensity for oligomerisation, accompanied by a more interconnected oligomerisation network, when compared to the receptor in the inactive state. Coupling of the active state to a mini Gs protein shifted the oligomerisation pattern. Oligomerisation is also sensitive to changes in local membrane environment, such as the packing density of GPCRs in a membrane patch, which enhanced oligomerisation, and removal of PIP2 from the lipid bilayer membrane which disfavoured oligomerisation. These results support combinatory allosteric modulation of GPCR oligomerisation whereby the receptor may generate a specific oligomerisation profile in response to its local environment in order to favour the formation of a specific supra-molecular signalling complex.GPCR_oligo_main_text_v16 biorxiv.docx 24-Jun-20

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“…The cholesterol consensus motif (CCM) is characterized by interactions with (W/Y)-(I/V/L)-(K/R) and (F/Y/R) 54 . By contrast, structures of membrane proteins (e.g., GPCRs and ion channels) determined in the presence of cholesterol/CHS have revealed interactions with "greasy hollows", which refers to pockets in the transmembrane portion lined with hydrophobic residues 30,57,58 .…”

Section: Cholesterol Binding Sites On Membrane Proteinsmentioning

confidence: 95%

Structural basis of GIRK2 channel modulation by cholesterol and PIP₂

Mathiharan

Glaaser

Zhao

et al. 2020

Preprint

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Significance/Impact:• GIRK2 is one of the primary GIRK channels in brain. Characterization of cholesterol binding in GIRK2 provides new therapeutic sites for modulating these channels.• Many ion channels are modulated by cholesterol, but the molecular basis of this modulation has been elusive.• First cryoEM structures of pore-forming Kir alpha subunit. Word counts: Abstract (136) -Main text (3048)ABSTRACT G protein-gated inwardly rectifying potassium (GIRK) channels play important roles in controlling cellular excitability in the heart and brain. While structural data begin to unravel the molecular basis for G protein and alcohol dependent activation of GIRK channels, little is known about the modulation by cholesterol. Here, we present cryo-electron microscopy (cryoEM) structures of GIRK2 in the presence and absence of the cholesterol analog cholesteryl hemisuccinate (CHS), and PIP 2 . The structures and their comparison reveal that CHS binds near PIP 2 in lipid-facing hydrophobic pockets of the transmembrane domain (TMD). CHS potentiates the effects of PIP 2 , which stabilizes the inter-domain region and promotes the engagement of the cytoplasmic domain (CTD) onto the transmembrane region. The results suggest that CHS acts as a positive allosteric modulator and identify novel therapeutic sites for modulating GIRK channels in the brain.* is shown with a dashed square.

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Lipid-Dependent Regulation of Ion Channels and G Protein–Coupled Receptors: Insights from Structures and Simulations

Cited by 132 publications

References 176 publications

The energetics of protein–lipid interactions as viewed by molecular simulations

The energetics of protein–lipid interactions as viewed by molecular simulations

Modulation of A2aR Oligomerisation by Conformational State and PIP₂Interactions Revealed by MD Simulations and Markov Models

Structural basis of GIRK2 channel modulation by cholesterol and PIP₂

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Lipid-Dependent Regulation of Ion Channels and G Protein–Coupled Receptors: Insights from Structures and Simulations

Cited by 132 publications

References 176 publications

The energetics of protein–lipid interactions as viewed by molecular simulations

The energetics of protein–lipid interactions as viewed by molecular simulations

Modulation of A2aR Oligomerisation by Conformational State and PIP2Interactions Revealed by MD Simulations and Markov Models

Structural basis of GIRK2 channel modulation by cholesterol and PIP2

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Product

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Modulation of A2aR Oligomerisation by Conformational State and PIP₂Interactions Revealed by MD Simulations and Markov Models

Structural basis of GIRK2 channel modulation by cholesterol and PIP₂