scholarly journals Lipid Interactions of a Ciliary Membrane TRP Channel: Simulation and Structural Studies of Polycystin-2 (PC2)

2019 ◽  
Author(s):  
Qinrui Wang ◽  
George Hedger ◽  
Prafulla Aryal ◽  
Mariana Grieben ◽  
Chady Nasrallah ◽  
...  
Keyword(s):  
Binding Site ◽  
Trp Channels ◽  
Md Simulations ◽  
Lipid Binding ◽  
Cryoelectron Microscopy ◽  
Trpv1 Channel ◽  
Lipid Interactions ◽  
Dynamics Simulations ◽  
Phosphatidylinositol Phosphates ◽  
Lipid Binding Site

AbstractPolycystin-2 (PC2) is a member of the TRPP subfamily of TRP channels and is present in ciliary membranes of the kidney. PC2 can be either homo-tetrameric, or heterotetrameric with PC1. PC2 shares a common transmembrane fold with other TRP channels, in addition to having a novel extracellular domain. Several TRP channels have been suggested to be regulated by lipids, including phosphatidylinositol phosphates (PIPs). We have combined molecular dynamics simulations with cryoelectron microscopy to explore possible lipid interactions sites on PC2. We propose that PC2 has a PIP-binding site close to the equivalent vanilloid/lipid-binding site in the TRPV1 channel. A 3.0 Å cryoelectron microscopy map reveals a binding site for cholesterol on PC2. Cholesterol interactions with the channel at this site are further characterized by MD simulations. These results help to position PC2 within an emerging model of the complex roles of lipids in the regulation and organization of ciliary membranes.

Interactions of peripheral proteins with model membranes as viewed by molecular dynamics simulations

2014 ◽  
Vol 42 (5) ◽  
pp. 1418-1424 ◽  
Author(s):  
Antreas C. Kalli ◽  
Mark S. P. Sansom
Keyword(s):  
Lipid Bilayers ◽  
Molecular Mechanisms ◽  
Phospholipid Composition ◽  
Md Simulations ◽  
Multiscale Simulation ◽  
Lipid Binding ◽  
Coarse Grained ◽  
Peripheral Proteins ◽  
Dynamics Simulations ◽  
Phosphatidylinositol Phosphates

Many cellular signalling and related events are triggered by the association of peripheral proteins with anionic lipids in the cell membrane (e.g. phosphatidylinositol phosphates or PIPs). This association frequently occurs via lipid-binding modules, e.g. pleckstrin homology (PH), C2 and four-point-one, ezrin, radixin, moesin (FERM) domains, present in peripheral and cytosolic proteins. Multiscale simulation approaches that combine coarse-grained and atomistic MD simulations may now be applied with confidence to investigate the molecular mechanisms of the association of peripheral proteins with model bilayers. Comparisons with experimental data indicate that such simulations can predict specific peripheral protein–lipid interactions. We discuss the application of multiscale MD simulation and related approaches to investigate the association of peripheral proteins which contain PH, C2 or FERM-binding modules with lipid bilayers of differing phospholipid composition, including bilayers containing multiple PIP molecules.

The N-Terminus is the Lipid-Binding Site of SAA: Supporting Evidence by MoAbs

1991 ◽  
pp. 83-86
Author(s):  
Yifat Ziq-Bachar ◽  
David Levartowsky ◽  
Mordechaipras ◽  
Alistair F. Strachan ◽  
Mati Fridkin ◽  
...  
Keyword(s):  
Binding Site ◽  
Lipid Binding ◽  
Supporting Evidence ◽  
N Terminus ◽  
Lipid Binding Site

Molecular simulations and lipid–protein interactions: potassium channels and other membrane proteins

2005 ◽  
Vol 33 (5) ◽  
pp. 916-920 ◽  
Author(s):  
M.S.P. Sansom ◽  
P.J. Bond ◽  
S.S. Deol ◽  
A. Grottesi ◽  
S. Haider ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Binding Site ◽  
Protein Interactions ◽  
Outer Membrane Proteins ◽  
Lipid Binding ◽  
Potassium Channel Kcsa ◽  
Head Groups ◽  
Arginine Residues ◽  
Lipid Protein Interactions ◽  
Dynamics Simulations

Molecular dynamics simulations may be used to probe the interactions of membrane proteins with lipids and with detergents at atomic resolution. Examples of such simulations for ion channels and for bacterial outer membrane proteins are described. Comparison of simulations of KcsA (an α-helical bundle) and OmpA (a β-barrel) reveals the importance of two classes of side chains in stabilizing interactions with the head groups of lipid molecules: (i) tryptophan and tyrosine; and (ii) arginine and lysine. Arginine residues interacting with lipid phosphate groups play an important role in stabilizing the voltage-sensor domain of the KvAP channel within a bilayer. Simulations of the bacterial potassium channel KcsA reveal specific interactions of phosphatidylglycerol with an acidic lipid-binding site at the interface between adjacent protein monomers. A combination of molecular modelling and simulation reveals a potential phosphatidylinositol 4,5-bisphosphate-binding site on the surface of Kir6.2.

Identification of the Lipid-Binding Site of Phosphatidylcholine-Transfer Protein with Phosphatidylcholine Analogs Containing Photactivable Carbene Precursors

1983 ◽  
Vol 132 (2) ◽  
pp. 441-449 ◽  
Author(s):  
Jan WESTERMAN ◽  
Karel W. A. WIRTZ ◽  
Theo BERKHOUT ◽  
Laurens L. M. DEENEN ◽  
Ramachandran RADHAKRISHNAN ◽  
...  
Keyword(s):  
Binding Site ◽  
Lipid Binding ◽  
Transfer Protein ◽  
Phosphatidylcholine Transfer Protein ◽  
Lipid Binding Site

scholarly journals Phospholipid-induced structural changes to an erythroid β spectrin ankyrin-dependent lipid-binding site

2008 ◽  
Vol 1778 (11) ◽  
pp. 2612-2620 ◽  
Author(s):  
Aleksander Czogalla ◽  
Krzysztof Grzymajło ◽  
Adam Jezierski ◽  
Aleksander F. Sikorski
Keyword(s):  
Binding Site ◽  
Structural Changes ◽  
Lipid Binding ◽  
Lipid Binding Site

scholarly journals Identification and assessment of cardiolipin interactions with E. coli inner membrane proteins

2021 ◽  
Author(s):  
Robin A. Corey ◽  
Wanling Song ◽  
Anna Duncan ◽  
T. Bertie Ansell ◽  
Mark S.P. Sansom ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Binding Site ◽  
Lipid Binding ◽  
Inner Membrane ◽  
Ample Evidence ◽  
Anionic Lipid ◽  
E Coli ◽  
Bacterial Proteins ◽  
Complex Protein ◽  
Dynamics Simulations

Integral membrane proteins are localised and/or regulated by lipids present in the surrounding bilayer. Whilst bacteria such as E. coli have relatively simple membranes when compared to eukaryotic cells, there is ample evidence that many bacterial proteins bind to specific lipids, especially the anionic lipid cardiolipin. Here, we apply molecular dynamics simulations to assess lipid binding to 42 different E. coli inner membrane proteins. Our data reveals a strong asymmetry between the membrane leaflets, with a marked increase of anionic lipid binding to the inner leaflet regions of membrane proteins, particularly for cardiolipin. From our simulations we identify over 700 independent cardiolipin binding sites, allowing us to identify the molecular basis of a prototypical cardiolipin binding site, which we validate against structures of bacterial proteins bound to cardiolipin. This allows us to construct a set of metrics for defining a high affinity cardiolipin binding site on (bacterial) membrane proteins, paving the way for a heuristic approach to defining more complex protein-lipid interactions.

scholarly journals Human TRPC5 structures reveal interaction of a xanthine-based TRPC1/4/5 inhibitor with a conserved lipid binding site

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
David J. Wright ◽  
Katie J. Simmons ◽  
Rachel M. Johnson ◽  
David J. Beech ◽  
Stephen P. Muench ◽  
...  
Keyword(s):  
Binding Site ◽  
Lipid Binding ◽  
Structural Basis ◽  
Chemical Probes ◽  
Endogenous Factors ◽  
Drug Candidates ◽  
Channel Regulation ◽  
Exogenous Factors ◽  
Translational Studies ◽  
Lipid Binding Site

AbstractTRPC1/4/5 channels are non-specific cation channels implicated in a wide variety of diseases, and TRPC1/4/5 inhibitors have recently entered clinical trials. However, fundamental and translational studies require a better understanding of TRPC1/4/5 channel regulation by endogenous and exogenous factors. Although several potent and selective TRPC1/4/5 modulators have been reported, the paucity of mechanistic insights into their modes-of-action remains a barrier to the development of new chemical probes and drug candidates. Xanthine-based modulators include the most potent and selective TRPC1/4/5 inhibitors described to date, as well as TRPC5 activators. Our previous studies suggest that xanthines interact with a, so far, elusive pocket of TRPC1/4/5 channels that is essential to channel gating. Here we report the structure of a small-molecule-bound TRPC1/4/5 channel—human TRPC5 in complex with the xanthine Pico145—to 3.0 Å. We found that Pico145 binds to a conserved lipid binding site of TRPC5, where it displaces a bound phospholipid. Our findings explain the mode-of-action of xanthine-based TRPC1/4/5 modulators, and suggest a structural basis for TRPC1/4/5 modulation by endogenous factors such as (phospho)lipids and Zn2+ ions. These studies lay the foundations for the structure-based design of new generations of TRPC1/4/5 modulators.

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