Lipid Interactions of a Ciliary Membrane TRP Channel: Simulation and Structural Studies of Polycystin-2

Wang, Qinrui; Corey, Robin A.; Hedger, George; Aryal, Prafulla; Grieben, M.; Nasrallah, Chady; Baronina, A.; Pike, Ashley C.W.; Shi, Jiye; Carpenter, E.P.; Sansom, Mark S.P.

doi:10.1016/j.str.2019.11.005

Cited by 44 publications

(46 citation statements)

References 140 publications

(170 reference statements)

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“…This can be compared with e.g. the free energy of interaction of PIP 2 with the transmembrane domain of a TRP channel (PC2) of ∼ −35 kJ mol −1 [32]. As can be seen in Figure 1C, the PIP 2 binding site is formed of a cluster of basic sidechains located close to the interface between the membrane and cytosolic regions.…”

Section: Binding Of Anionic Lipids To Membrane Proteinsmentioning

confidence: 98%

“…Similarly, atomistic simulations employing molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) calculations suggest binding energies of −3, −7.5, and −10.5 kJ mol −1 of cholesterol to three distinct sites on Kir2.1 [69]. Recent CG simulations based on cholesterol bound to the ciliary TRP channel PC2 [32] yielded an interaction free energy of −12 kJ mol −1 . Thus, these systems also reveal relatively modest binding free energies for cholesterol.…”

Section: Binding Of Cholesterol To Gpcrs and Other Membrane Proteinsmentioning

confidence: 99%

“…including e.g. phosphatidylinositol (4,5) bis-phosphate (PIP 2 ) bound to Kir channels [27,28]; cardiolipin (CDL) bound to the ADP/ATP carrier [29,30], and to the LeuT transporter [1]; and PIP 2 bound to Class A GPCRS [31] and to TRP channels [32]. MD simulations can also provide information on local enrichment of various lipid species in the bilayer around a given membrane protein [33].…”

Section: Protein-lipid Interactions: Structures and Simulationsmentioning

confidence: 99%

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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: Binding Of Anionic Lipids To Membrane Proteinsmentioning

confidence: 98%

Section: Binding Of Cholesterol To Gpcrs and Other Membrane Proteinsmentioning

confidence: 99%

Section: Protein-lipid Interactions: Structures and Simulationsmentioning

confidence: 99%

See 1 more Smart Citation

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

Corey

Stansfeld

Sansom

2019

Biochemical Society Transactions

Self Cite

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“…In Figure 1C, we show the obtained local occupancy map. Interesting, both the occupancy and A maps show low values in the regions occupied by detergent densities, lipid densities and cholesterol densities (please see Figure 2 in (Wang, Corey et al 2020)), indicating the presence of compositional variability in these regions and low signal at 15 Å.…”

Section: Polycystin-2 (Pc2) Trp Channelmentioning

confidence: 98%

“…First, we analysed a single-particle reconstruction of the polycystin-2 (PC2) TRP channel (EMDataBank: EMD-10418) (Wang, Corey et al 2020). In this case, we focussed on showing the capacity of our LocSpiral approach, though, for the sake of consistency, we also show results of our obtained B-factor and occupancy maps.…”

Section: Polycystin-2 (Pc2) Trp Channelmentioning

confidence: 99%

Local computational methods to improve the interpretability and analysis of cryo-EM maps

Kaur

Gómez-Blanco

Khalifa

et al. 2020

Preprint

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Cryo-electron microscopy (cryo-EM) maps usually show heterogeneous distributions of B-factors and electron density occupancies and are typically B-factor sharpened to improve their contrast and interpretability at high-resolutions. However, 'over-sharpening' due to the application of a single global B-factor can distort processed maps causing connected densities to appear broken and disconnected. This issue limits the interpretability of cryo-EM maps, i.e. ab initio modelling.In this work, we propose 1) approaches to enhance high-resolution features of cryo-EM maps, while preventing map distortions and 2) methods to obtain local B-factors and electron density occupancy maps. These algorithms have as common link the use of the spiral phase transformation and are called LocSpiral, LocBSharpen, LocBFactor and LocOccupancy. Our results, which

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Ciliary membrane, localised lipid modification and cilia function

Dutta

Ray

2022

Journal Cellular Physiology

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Cilium, a tiny microtubule‐based cellular appendage critical for cell signalling and physiology, displays a large variety of receptors. The composition and turnover of ciliary lipids and receptors determine cell behaviour. Due to the exclusion of ribosomal machinery and limited membrane area, a cilium needs adaptive logistics to actively reconstitute the lipid and receptor compositions during development and differentiation. How is this dynamicity generated? Here, we examine whether, along with the Intraflagellar‐Transport, targeted changes in sector‐wise lipid composition could control the receptor localisation and functions in the cilia. We discuss how an interplay between ciliary lipid composition, localised lipid modification, and receptor function could contribute to cilia growth and signalling. We argue that lipid modification at the cell‐cilium interface could generate an added thrust for a selective exchange of membrane lipids and the transmembrane and membrane‐associated proteins.

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Lipid Interactions of a Ciliary Membrane TRP Channel: Simulation and Structural Studies of Polycystin-2

Cited by 44 publications

References 140 publications

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

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

Local computational methods to improve the interpretability and analysis of cryo-EM maps

Ciliary membrane, localised lipid modification and cilia function

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