scholarly journals How curvature-generating proteins build scaffolds on membrane nanotubes

2016 ◽  
Vol 113 (40) ◽  
pp. 11226-11231 ◽  
Author(s):  
Mijo Simunovic ◽  
Emma Evergren ◽  
Ivan Golushko ◽  
Coline Prévost ◽  
Henri-François Renard ◽  
...  
Keyword(s):  
Lipid Membranes ◽  
Coarse Grained ◽  
Molecular Scaffolds ◽  
Bar Domain ◽  
Membrane Tube ◽  
Bar Domain Proteins ◽  
Specific Localization ◽  
A Cell ◽  
Dynamics Simulations ◽  
Cooperative Assembly

Bin/Amphiphysin/Rvs (BAR) domain proteins control the curvature of lipid membranes in endocytosis, trafficking, cell motility, the formation of complex subcellular structures, and many other cellular phenomena. They form 3D assemblies that act as molecular scaffolds to reshape the membrane and alter its mechanical properties. It is unknown, however, how a protein scaffold forms and how BAR domains interact in these assemblies at protein densities relevant for a cell. In this work, we use various experimental, theoretical, and simulation approaches to explore how BAR proteins organize to form a scaffold on a membrane nanotube. By combining quantitative microscopy with analytical modeling, we demonstrate that a highly curving BAR protein endophilin nucleates its scaffolds at the ends of a membrane tube, contrary to a weaker curving protein centaurin, which binds evenly along the tube’s length. Our work implies that the nature of local protein–membrane interactions can affect the specific localization of proteins on membrane-remodeling sites. Furthermore, we show that amphipathic helices are dispensable in forming protein scaffolds. Finally, we explore a possible molecular structure of a BAR-domain scaffold using coarse-grained molecular dynamics simulations. Together with fluorescence microscopy, the simulations show that proteins need only to cover 30–40% of a tube’s surface to form a rigid assembly. Our work provides mechanical and structural insights into the way BAR proteins may sculpt the membrane as a high-order cooperative assembly in important biological processes.

scholarly journals Curvature induction and sensing of the F-BAR protein Pacsin1 on lipid membranes via molecular dynamics simulations

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Md. Iqbal Mahmood ◽  
Hiroshi Noguchi ◽  
Kei-ichi Okazaki
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Lipid Membranes ◽  
Lipid Membrane ◽  
Complex Structure ◽  
Membrane Curvature ◽  
Coarse Grained ◽  
Lateral Interaction ◽  
Bar Domain ◽  
Dynamics Simulations

Abstract F-Bin/Amphiphysin/Rvs (F-BAR) domain proteins play essential roles in biological processes that involve membrane remodelling, such as endocytosis and exocytosis. It has been shown that such proteins transform the lipid membrane into tubes. Notably, Pacsin1 from the Pacsin/Syndapin subfamily has the ability to transform the membrane into various morphologies: striated tubes, featureless wide and thin tubes, and pearling vesicles. The molecular mechanism of this interesting ability remains elusive. In this study, we performed all-atom (AA) and coarse-grained (CG) molecular dynamics simulations to investigate the curvature induction and sensing mechanisms of Pacsin1 on a membrane. From AA simulations, we show that Pacsin1 has internal structural flexibility. In CG simulations with parameters tuned from the AA simulations, spontaneous assembly of two Pacsin1 dimers through lateral interaction is observed. Based on the complex structure, we show that the regularly assembled Pacsin1 dimers bend a tensionless membrane. We also show that a single Pacsin1 dimer senses the membrane curvature, binding to a buckled membrane with a preferred curvature. These results provide molecular insights into polymorphic membrane remodelling.

scholarly journals A putative N-BAR-domain protein is crucially required for the development of hyphae tip appressorium-like structure and its plant infection in Magnaporthe oryzae

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Lili Lin ◽  
Xiaomin Chen ◽  
Ammarah Shabbir ◽  
Si Chen ◽  
Xuewen Chen ◽  
...  
Keyword(s):  
Magnaporthe Oryzae ◽  
Lipid Membranes ◽  
Cellular Membrane ◽  
Gene Replacement ◽  
Bar Domain ◽  
Plant Infection ◽  
Expression Of Genes ◽  
Peripheral Proteins ◽  
Bar Domain Proteins ◽  
Replacement Technique

Abstract Membrane remodeling modulates many biological processes. The binding of peripheral proteins to lipid membranes results in membrane invaginations and protrusions, which regulate essential intra-cellular membrane and extra-cellular trafficking events. Proteins that bind and re-shape bio-membranes have been identified and extensively investigated. The Bin/Amphiphysin/Rvs (BAR) domain proteins are crescent-shape and play a conserved role in tubulation and sculpturing of cell membranes. We deployed targeted gene replacement technique to functionally characterize two hypothetical proteins (MoBar-A and MoBar-B) containing unitary N-BAR domain in Magnaporthe oryzae. The results obtained from phenotypic examinations showed that MoBAR-A deletion exerted a significant reduction in the growth of the defective ∆Mobar-A strain. Also, MoBAR-A disruption exclusively compromised hyphae-mediated infection. Additionally, the targeted replacement of MoBAR-A suppressed the expression of genes associated with the formation of hyphae tip appressorium-like structure in M. oryzae. Furthermore, single as well as combined deletion of MoBAR-A and MoBAR-B down-regulated the expression of nine different membrane-associated genes. From these results, we inferred that MoBAR-A plays a key and unique role in the pathogenesis of M. oryzae through direct or indirect regulation of the development of appressorium-like structures developed by hyphae tip. Taken together, these results provide unique insights into the direct contribution of the N-BAR domain proteins to morphological, reproduction, and infectious development of M. oryzae.

scholarly journals Adsorption Of Bar-domain Proteins To Charged Lipid Membranes Causes Deformations And Lipid Demixing

2009 ◽  
Vol 96 (3) ◽  
pp. 95a
Author(s):  
George Khelashvili ◽  
Daniel Harries ◽  
Harel Weinstein
Keyword(s):  
Lipid Membranes ◽  
Bar Domain ◽  
Bar Domain Proteins

scholarly journals Inverse design of cholesterol attracting transmembrane helices reveals a paradoxical role of hydrophobic length

2021 ◽  
Author(s):  
Jeroen Methorst ◽  
Niek van Hilten ◽  
Herre Jelger Risselada
Keyword(s):  
Molecular Dynamics ◽  
Lipid Membranes ◽  
Transmembrane Domain ◽  
Optimal Solution ◽  
Molecular Shape ◽  
Global Optimum ◽  
Coarse Grained ◽  
Hydrophobic Core ◽  
Recognition Motifs ◽  
Dynamics Simulations

The occurrence of linear cholesterol-recognition motifs in alpha-helical transmembrane domains has long been debated. Here, we demonstrate the ability of a genetic algorithm guided by coarse-grained molecular dynamics simulations---a method coined evolutionary molecular dynamics (evo-MD)---to directly resolve the sequence which maximally attracts/sorts cholesterol within a single-pass alpha-helical transmembrane domain (TMDs). We illustrate that the evolutionary landscape of cholesterol attraction in membrane proteins is characterized by a sharp, well-defined global optimum. Surprisingly, this optimal solution features an unusual short hydrophobic block, consisting of typically only eight short chain hydrophobic amino acids, surrounded by three successive lysines. Owing to the membrane thickening effect of cholesterol, cholesterol-enriched ordered phases favor TMDs characterized by a long rather than a short hydrophobic length. However, this short hydrophobic pattern evidently offers a pronounced net advantage for the binding of free cholesterol in both coarse-grained and atomistic simulations. Attraction is mediated by the unique ability of cholesterol to snorkel within the hydrophobic core of the membrane and thereby shield deeply located lysines from the unfavorable hydrophobic surrounding. Since this mechanism of attraction is of a thermodynamic nature and is not based on molecular shape specificity, a large diversity of sub-optimal cholesterol attracting sequences can exist. The puzzling sequence variability of proposed linear cholesterol-recognition motifs is thus consistent with sub-optimal, unspecific binding of cholesterol. Importantly, since evo-MD uniquely enables the targeted design of recognition motifs for distinct fluid lipid membranes, we foresee wide applications for evo-MD in the biological and biomedical fields.

scholarly journals Molecular dynamics simulations of membrane deformation induced by the amphiphilic helices of Epsin, Sar1p and Arf1

2017 ◽  
Author(s):  
Zhen-lu Li
Keyword(s):  
Lipid Membranes ◽  
Critical Role ◽  
Membrane Curvature ◽  
Coarse Grained ◽  
Insertion Depth ◽  
Membrane Deformation ◽  
Specific Distribution ◽  
Amphiphilic Helix ◽  
Coarse Grained Simulations ◽  
Dynamics Simulations

AbstractThe N-terminal amphiphilic helices of proteins Epsin, Sar1p and Arf1 play a critical role in initiating membrane deformation. We present here the study of the interactions of these amphiphilic helices with the lipid membranes by combining the all-atom and coarse-grained simulations. In the all-atom simulations, we find that the amphiphilic helices of Epsin and Sar1p have a shallower insertion depth into the membrane compared to the amphiphilic helix of Arf1, but remarkably, the amphiphilic helices of Epsin and Sar1p induce higher asymmetry in the lipid packing between the two monolayers of the membrane. The insertion depth of amphiphilic helix into the membrane is determined not only by the overall hydrophobicity but also by the specific distribution of polar and non-polar residues along the helix. To directly compare their ability of deforming the membrane, we further apply coarse-grained simulations to investigate the membranes deformation under the insertion of multiple helices. Importantly, it is found that the amphiphilic helices of Epsin and Sar1p generate a larger membrane curvature than that of Arf1, in accord with the experimental results qualitatively. These findings enhance our understanding of the molecular mechanism of the protein-driven membrane remodeling.

scholarly journals Polymer-like model to study the dynamics of dynamin filaments on deformable membrane tubes

2019 ◽  
Author(s):  
Jeffrey K. Noel ◽  
Frank Noé ◽  
Oliver Daumke ◽  
Alexander S. Mikhailov
Keyword(s):  
Thermal Fluctuations ◽  
Membrane Curvature ◽  
Coarse Grained ◽  
Chain Model ◽  
Dependent Manner ◽  
Membrane Tube ◽  
Elastic Filament ◽  
Intrinsic Shape ◽  
Deformable Membrane ◽  
Dynamics Simulations

AbstractPeripheral membrane proteins with intrinsic curvature can act both as sensors of membrane curvature and shape modulators of the underlying membranes. A well-studied example of such proteins is the mechano-chemical GTPase dynamin that assembles into helical filaments around membrane tubes and catalyzes their scission in a GTPase-dependent manner. It is known that the dynamin coat alone, without GTP, can constrict membrane tubes to radii of about 10 nanometers, indicating that the intrinsic shape and elasticity of dynamin filaments should play an important role in membrane remodeling. However, molecular and dynamic understanding of the process is lacking. Here, we develop a dynamical polymer-chain model for a helical elastic filament bound on a deformable membrane tube of conserved mass, accounting for thermal fluctuations in the filament and lipid flows in the membrane. The model is based on a locally-cylindrical helix approximation for dynamin. We obtain the elastic parameters of the dynamin filament by molecular dynamics simulations of its tetrameric building block and also from coarse-grained structure-based simulations of a 17-dimer filament. The results show that the stiffness of dynamin is comparable to that of the membrane. We determine equilibrium shapes of the filament and the membrane, and find that mostly the pitch of the filament, not its radius, is sensitive to variations in membrane tension and stiffness. The close correspondence between experimental estimates of the inner tube radius and those predicted by the model suggests that dynamin’s “stalk” region is responsible for its GTP-independent membrane-shaping ability. The model paves the way for future mesoscopic modeling of dynamin with explicit motor function.

scholarly journals Cholesterol Oxidation Modulates the Formation of Liquid-Ordered Domains in Model Membranes

2021 ◽  
Author(s):  
Paul Smith ◽  
Peter G Petrov ◽  
Christian D Lorenz
Keyword(s):  
Lipid Membranes ◽  
Coarse Grained ◽  
Cholesterol Oxidation ◽  
Phosphatidylinositol 3 Kinase ◽  
Single Chemical ◽  
Liquid Ordered ◽  
Dynamics Simulations ◽  
Lateral Organization ◽  
Molecular Description ◽  
Liquid Liquid Phase Separation

7-ketocholesterol (KChol) is one of the most cytotoxic oxysterols found in the plasma membrane, and increased levels of KChol are associated with numerous pathologies. It is thought to induce apoptosis via inactivation of the phosphatidylinositol 3-kinase/Akt signaling pathway - a pathway that depends on lipid-rafts as signaling platforms. By means of coarse-grained molecular dynamics simulations, we demonstrate that KChol disrupts the liquid-liquid phase separation seen in an equimolar mixture of (dipalmitoylphosphatidylcholine) DPPC, (dioleoylphosphatidylcholine) DOPC, and Cholesterol (Chol). This disruption occurs via two mechanisms: i) KChol adopts a wider range of orientations with the membrane, which disrupts the packing of neighboring lipids and ii) KChol has no preference for DPPC over DOPC, which is the main driving force for lateral demixing in DPPC/DOPC/Chol membranes. This provides a molecular description of the means by which KChol induces apoptosis, and illustrates that a single chemical substitution to cholesterol can have a profound impact on the lateral organization of lipid membranes.

scholarly journals Mechanistic basis for motor-driven membrane constriction by dynamin

2020 ◽  
Author(s):  
Oleg Ganichkin ◽  
Renee Vancraenenbroeck ◽  
Gabriel Rosenblum ◽  
Hagen Hofmann ◽  
Alexander S. Mikhailov ◽  
...  
Keyword(s):  
Single Molecule ◽  
Structural Model ◽  
Molecular Motor ◽  
Coarse Grained ◽  
Gtp Hydrolysis ◽  
Single Molecule Fret ◽  
Membrane Tube ◽  
Mechanistic Basis ◽  
Dynamics Simulations ◽  
Gtpase Cycle

AbstractThe mechano-chemical GTPase dynamin assembles on membrane necks of clathrin-coated vesicles into helical oligomers that constrict and eventually cleave the necks in a GTP-dependent way. It remains not clear whether dynamin achieves this via molecular motor activity and, if so, by what mechanism. Here, we used ensemble kinetics, single-molecule FRET and molecular dynamics simulations to characterize dynamin’s GTPase cycle and determine the powerstroke strength. The results were incorporated into a coarse-grained structural model of dynamin filaments on realistic membrane templates. Working asynchronously, dynamin’s motor modules were found to collectively constrict a membrane tube. Force is generated by motor dimers linking adjacent helical turns and constriction is accelerated by their strain-dependent dissociation. Consistent with experiments, less than a second is needed to constrict a membrane tube to the hemi-fission radius. Thus, a membrane remodeling mechanism relying on cooperation of molecular ratchet motors driven by GTP hydrolysis has been revealed.

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