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Mark S P Sansom - One of the best experts on this subject based on the ideXlab platform.

  • association of Peripheral Membrane Proteins with Membranes free energy of binding of grp1 ph domain with phosphatidylinositol phosphate containing model bilayers
    Journal of Physical Chemistry Letters, 2016
    Co-Authors: Fiona B Naughton, Antreas C Kalli, Mark S P Sansom
    Abstract:

    Understanding the energetics of Peripheral protein–Membrane interactions is important to many areas of biophysical chemistry and cell biology. Estimating free-energy landscapes by molecular dynamics (MD) simulation is challenging for such systems, especially when Membrane recognition involves complex lipids, e.g., phosphatidylinositol phosphates (PIPs). We combined coarse-grained MD simulations with umbrella sampling to quantify the binding of the well-explored GRP1 pleckstrin homology (PH) domain to model Membranes containing PIP molecules. The experimentally observed preference of GRP1-PH for PIP3 over PIP2 was reproduced. Mutation of a key residue (K273A) within the canonical PIP-binding site significantly reduced the free energy of PIP binding. The presence of a noncanonical PIP-interaction site, observed experimentally in other PH domains but not previously in GRP1-PH, was also revealed. These studies demonstrate how combining coarse-grained simulations and umbrella sampling can unmask the molecular ...

  • investigating the interactions of Peripheral Membrane Proteins with model Membranes using high throughput molecular dynamics simulations
    Biophysical Journal, 2016
    Co-Authors: Antreas C Kalli, Eiji Yamamoto, Fiona B Naughton, Mark S P Sansom
    Abstract:

    Many signaling and trafficking events in cells are regulated by the binding of Peripheral Membrane Proteins to specific lipids (e.g. phosphatidylinositol phosphates; PIPs) in cell Membranes. This binding frequently occurs via lipid-binding modules such as the Pleckstrin Homology (PH) domain present in many Peripheral Proteins. It remains challenging to investigate the molecular mechanisms and the energetics by which these lipid-binding modules associate with lipid Membranes. Here we will discuss the application of a high-throughput molecular dynamics simulation approach to investigate the association of Peripheral Membrane Proteins with lipid bilayers of differing phospholipid composition. This computational approach was designed to perform large number of coarse-grained molecular dynamics simulation. It therefore enables detailed investigation of the molecular mechanisms by which Peripheral Membranes Proteins associate with model Membranes and construction of the energy landscapes for their binding to model Membrane surfaces. In particular, we have determined the mechanism of localization of different PH domains to a PIP-containing bilayer and we have examined the extent of conservation/variation of the interactions of different members of the PH domain family with the lipids. The PH/PIP complexes obtained from our simulations are in good agreement with available structural data. By applying a potential of mean force approach we can also calculate the energy of binding of a PH domain to a PIP-containing bilayer. Additionally, we have extended our studies to other Peripheral Membrane Proteins that contain FERM, PH, and C2 lipid-binding domains. Our results suggest novel models for the association and interactions of these lipid-binding domains with Membranes.

  • Ras Proteins, Lipid Domains and Palmitoylation: Modelling the Complex Interactions between Ras Proteins and Cell Membranes
    Biophysical Journal, 2013
    Co-Authors: Philip W. Fowler, Elizabeth E. Jefferys, Mark S P Sansom
    Abstract:

    The Ras Proteins have been repeatedly identified as key components in a wide range of cell signalling networks. The classical Ras Proteins all have at least one C-terminal lipid anchor which is essential for both their Membrane localisation within the cell and their biological activity. Coarse-grained molecular dynamics simulations have, over the past few years, been established as a reliable technique for examining protein-lipid interactions, both for integral and more recently for Peripheral Membrane Proteins. We have used this technique to examine how Ras Proteins bind to a model phase-separated Membrane containing cholesterol. In particular, we wish to explore how Ras Proteins may cluster and what effect they have on the nature and size of lipid domains. Each of the classical Ras Proteins has a farnesyl lipid anchor, but HRas and NRas may also be (reversibly) palmitoylated. We have therefore examined the effect of removing one (or in the case of HRas, both) palmitoyl tails upon their interactions with Membranes.

Matthias Weiss - One of the best experts on this subject based on the ideXlab platform.

  • Mesoscopic Simulations of Membrane Protein Trafficking and Signal Transduction Across Membranes
    Biophysical Journal, 2020
    Co-Authors: Diana Morozova, Gernot Guigas, Matthias Weiss
    Abstract:

    Palmitoylation is a frequent posttranslational modification that triggers the Membrane association of soluble Proteins. Besides those Peripheral Membrane Proteins (PMPs) also many transMembrane Proteins are subject to lipid modifications, hence indicating that these Membrane anchors may also regulate the trafficking of transMembrane Proteins. Using coarse-grained Membrane simulations we find that palmitoylation indeed significantly alters the tilting of transMembrane Proteins with respect to the bilayer normal. Cluster formation and partitioning behavior due to hydrophobic mismatching with the surrounding lipid bilayer is also altered, therefore allowing for ample possibilities to regulate the trafficking of transMembrane Proteins via palmitoylation. Using the same simulation approach, we also have studied the trafficking of Peripheral Membrane Proteins (PMPs). In particular, we have observed a cross-leaflet oligomerization of PMPs due to Membrane mediated attraction. The strength of this effect is determined by the radii and Membrane anchor lengths of the involved PMPs. Since both of these might be altered, for example by ligand binding, the observed cross-leaflet oligomerization may be the fundamental process by which PMPs can trigger an intracellular signalling cascade without the need for accessory transMembrane factors.

  • influence of organelle geometry on the apparent binding kinetics of Peripheral Membrane Proteins
    Physical Review E, 2015
    Co-Authors: Julia Hoffmann, Rolf Fickentscher, Matthias Weiss
    Abstract:

    : Information processing in living cells frequently involves an exchange of Peripheral Membrane Proteins between the cytosol and organelle Membranes. The typical time scale τ of these association-dissociation cycles is commonly quantified in vivo via fluorescence recovery after photobleaching (FRAP). Contrary to common assumptions, we show here that τ values determined by FRAP depend on the size and number of target structures. Hence, FRAP times alone are insufficient to draw conclusions about the Proteins' binding kinetics. In contrast, extracting primary molecular association and dissociation rates from FRAP approaches provides a size-independent and therefore robust measure for the Proteins' binding kinetics. We support our theoretical considerations with experiments on the small GTPase Arf-1 that transiently associates with Golgi Membranes: While Arf-1 recovery times in untreated cells and in cells with disrupted microtubules are significantly different, the molecular kinetic rates are shown to be the same in both cases.

  • dynamic structure formation of Peripheral Membrane Proteins
    PLOS Computational Biology, 2011
    Co-Authors: Diana Morozova, Gernot Guigas, Matthias Weiss
    Abstract:

    Using coarse-grained Membrane simulations we show here that Peripheral Membrane Proteins can form a multitude of higher-order structures due to Membrane-mediated interactions. Peripheral Membrane Proteins characteristically perturb the lipid bilayer in their vicinity which supports the formation of protein assemblies not only within the same but surprisingly also across opposing leaflets of a bilayer. In addition, we also observed the formation of lipid-protein domains on heteregeneous Membranes. The clustering ability of Proteins, as quantified via the potential of mean force, is enhanced when radius and hydrophobic penetration depth of the Proteins increases. Based on our data, we propose that Membrane-mediated cluster formation of Peripheral Proteins supports protein assembly in vivo and hence may play a pivotal role in the formation of templates for signaling cascades and in the emergence of transport intermediates in the secretory pathway.

Louis M Kunkel - One of the best experts on this subject based on the ideXlab platform.

  • cloning and characterization of the human homologue of a dystrophin related phosphoprotein found at the torpedo electric organ post synaptic Membrane
    Human Molecular Genetics, 1996
    Co-Authors: Helene M Sadouletpuccio, Jonathan B Cohen, Tejvir S Khurana, Louis M Kunkel
    Abstract:

    : Dystrophin is the protein product which is absent in Duchenne muscular dystrophy (DMD). In mammalian skeletal muscle, dystrophin is found in association with several integral and Peripheral Membrane Proteins, forming a complex known as the dystrophin glycoprotein complex (DGC). In an expressed sequence tag (EST) database search to identify new dystrophin related genes, we isolated EST00891 which showed 57% homology to the cysteine-rich domain of dystrophin and localized to 18q12.1-12.2. This EST is also highly homologous (90%) to the Torpedo californica post-synaptic 87 kDa phosphoprotein. Screening human adult brain and skeletal muscle cDNA libraries with this EST resulted in cloning multiple cDNAs which encode several splice forms all homologous to the C-terminal domain of dystrophin. The largest open reading frame isolated shows 94% homology (86% identity) to the Torpedo 87 kDa protein and 50% homology to the cysteine-rich and carboxy-terminal domains of dystrophin. The other cDNAs isolated encode smaller splice forms of this gene which we have named dystrobrevin. The tissue distribution of dystrobrevin mRNA shows five distinct transcripts which are preferentially expressed between different tissues. In addition, antibodies against either the Torpedo 87 kDa protein or human dystrobrevin demonstrate that at least three of the splice forms are translated as Proteins in human brain tissue extracts.

Jennifer Greaves - One of the best experts on this subject based on the ideXlab platform.

Sue L Jaspersen - One of the best experts on this subject based on the ideXlab platform.

  • changes in the nuclear envelope environment affect spindle pole body duplication in saccharomyces cerevisiae
    Genetics, 2010
    Co-Authors: Keren L Witkin, Jennifer M Friederichs, Orna Cohenfix, Sue L Jaspersen
    Abstract:

    The Saccharomyces cerevisiae nuclear Membrane is part of a complex nuclear envelope environment also containing chromatin, integral and Peripheral Membrane Proteins, and large structures such as nuclear pore complexes (NPCs) and the spindle pole body. To study how properties of the nuclear Membrane affect nuclear envelope processes, we altered the nuclear Membrane by deleting the SPO7 gene. We found that spo7Δ cells were sickened by the mutation of genes coding for spindle pole body components and that spo7Δ was synthetically lethal with mutations in the SUN domain gene MPS3. Mps3p is required for spindle pole body duplication and for a variety of other nuclear envelope processes. In spo7Δ cells, the spindle pole body defect of mps3 mutants was exacerbated, suggesting that nuclear Membrane composition affects spindle pole body function. The synthetic lethality between spo7Δ and mps3 mutants was suppressed by deletion of specific nucleoporin genes. In fact, these gene deletions bypassed the requirement for Mps3p entirely, suggesting that under certain conditions spindle pole body duplication can occur via an Mps3p-independent pathway. These data point to an antagonistic relationship between nuclear pore complexes and the spindle pole body. We propose a model whereby nuclear pore complexes either compete with the spindle pole body for insertion into the nuclear Membrane or affect spindle pole body duplication by altering the nuclear envelope environment.