scholarly journals The Functional Significance of Hydrophobic Residue Distribution in Bacterial Beta-Barrel Transmembrane Proteins

Membranes ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 580
Author(s):  
Irena Roterman ◽  
Katarzyna Stapor ◽  
Piotr Fabian ◽  
Leszek Konieczny
Keyword(s):  
Membrane Proteins ◽  
Lipid Membrane ◽  
Hydrophobic Interactions ◽  
Transmembrane Proteins ◽  
Soluble Proteins ◽  
Aqueous Environment ◽  
Hydrophobic Core ◽  
Hydrophobic Residues ◽  
Beta Barrel ◽  
Gauss Function

β-barrel membrane proteins have several important biological functions, including transporting water and solutes across the membrane. They are active in the highly hydrophobic environment of the lipid membrane, as opposed to soluble proteins, which function in a more polar, aqueous environment. Globular soluble proteins typically have a hydrophobic core and a polar surface that interacts favorably with water. In the fuzzy oil drop (FOD) model, this distribution is represented by the 3D Gauss function (3DG). In contrast, membrane proteins expose hydrophobic residues on the surface, and, in the case of ion channels, the polar residues face inwards towards a central pore. The distribution of hydrophobic residues in membrane proteins can be characterized by means of 1–3DG, a complementary 3D Gauss function. Such an analysis was carried out on the transmembrane proteins of bacteria, which, despite the considerable similarities of their super-secondary structure (β-barrel), have highly differentiated properties in terms of stabilization based on hydrophobic interactions. The biological activity and substrate specificity of these proteins are determined by the distribution of the polar and nonpolar amino acids. The present analysis allowed us to compare the ways in which the different proteins interact with antibiotics and helped us understand their relative importance in the development of the resistance mechanism. We showed that beta barrel membrane proteins with a hydrophobic core interact less strongly with the molecules they transport.

scholarly journals Computational Study of the Interaction of a PEGylated Hyperbranched Polymer/Doxorubicin Complex with a Bilipid Membrane

Fluids ◽  
2019 ◽  
Vol 4 (1) ◽  
pp. 17 ◽  
Author(s):  
Prodromos Arsenidis ◽  
Kostas Karatasos
Keyword(s):  
Hyperbranched Polymer ◽  
Lipid Membrane ◽  
Hydrophobic Interactions ◽  
Computational Study ◽  
Translational Motion ◽  
Spatial Arrangement ◽  
Aqueous Environment ◽  
Drug Molecules ◽  
Dynamics Simulations ◽  
A Charge

Fully atomistic molecular dynamics simulations are employed to study in detail the interactions between a complex comprised by a PEGylated hyperbranched polyester (HBP) and doxorubicin molecules, with a model dipalmitoylphosphatidylglycerol membrane in an aqueous environment. The effects of the presence of the lipid membrane in the drug molecules’ spatial arrangement were examined in detail and the nature of their interaction with the latter were discussed and quantified where possible. It was found that a partial migration of the drug molecules towards the membrane’s surface takes place, driven either by hydrogen-bonding (for the protonated drugs) or by hydrophobic interactions (for the neutral drug molecules). The clustering behavior of the drug molecules appeared to be enhanced in the presence of the membrane, while the development of a charge excess close to the surface of the hyperbranched polymer and of the lipid membrane was observed. The uneven charge distribution created an effective overcharging of the HBP/drug complex and the membrane/drug surface. The translational motion of the drug molecules was found to be strongly affected by the presence of the membrane. The extent of the observed changes depended on the charge of the drug molecule. The build-up of the observed charge excesses close to the surface of the polymeric host and the membrane, together with the changes in the diffusional behavior of the drug molecules are of particular interest. Both phenomena could be important at the latest stages of the liposomal disruption and the release of the drug cargo in formulations based on relevant liposomal carriers.

scholarly journals Membrane Protein Stabilization Strategies for Structural and Functional Studies

Membranes ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 155
Author(s):  
Ekaitz Errasti-Murugarren ◽  
Paola Bartoccioni ◽  
Manuel Palacín
Keyword(s):  
Membrane Proteins ◽  
Membrane Protein ◽  
Lipid Membrane ◽  
Protein Stabilization ◽  
New Drugs ◽  
Cell Physiology ◽  
Protein Preparation ◽  
Functional Studies ◽  
Membrane Protein Stability ◽  
Druggable Targets

Accounting for nearly two-thirds of known druggable targets, membrane proteins are highly relevant for cell physiology and pharmacology. In this regard, the structural determination of pharmacologically relevant targets would facilitate the intelligent design of new drugs. The structural biology of membrane proteins is a field experiencing significant growth as a result of the development of new strategies for structure determination. However, membrane protein preparation for structural studies continues to be a limiting step in many cases due to the inherent instability of these molecules in non-native membrane environments. This review describes the approaches that have been developed to improve membrane protein stability. Membrane protein mutagenesis, detergent selection, lipid membrane mimics, antibodies, and ligands are described in this review as approaches to facilitate the production of purified and stable membrane proteins of interest for structural and functional studies.

scholarly journals Craniofacial Diseases Caused by Defects in Intracellular Trafficking

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 726
Author(s):  
Chung-Ling Lu ◽  
Jinoh Kim
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Intracellular Trafficking ◽  
Critical Role ◽  
Treatment Strategies ◽  
Soluble Proteins ◽  
Genes Encoding ◽  
Membrane Bound ◽  
Signaling Receptors ◽  
Craniofacial Morphogenesis

Cells use membrane-bound carriers to transport cargo molecules like membrane proteins and soluble proteins, to their destinations. Many signaling receptors and ligands are synthesized in the endoplasmic reticulum and are transported to their destinations through intracellular trafficking pathways. Some of the signaling molecules play a critical role in craniofacial morphogenesis. Not surprisingly, variants in the genes encoding intracellular trafficking machinery can cause craniofacial diseases. Despite the fundamental importance of the trafficking pathways in craniofacial morphogenesis, relatively less emphasis is placed on this topic, thus far. Here, we describe craniofacial diseases caused by lesions in the intracellular trafficking machinery and possible treatment strategies for such diseases.

scholarly journals Basic Residue Clusters in Intrinsically Disordered Regions of Peripheral Membrane Proteins: Modulating 2D Diffusion on Cell Membranes

Physchem ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 152-162
Author(s):  
Miquel Pons
Keyword(s):  
Membrane Proteins ◽  
Electrostatic Interactions ◽  
Lipid Membrane ◽  
Conformational Ensemble ◽  
Basic Residue ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Peripheral Membrane Proteins ◽  
Charged Residues ◽  
Disordered Regions

A large number of peripheral membrane proteins transiently interact with lipids through a combination of weak interactions. Among them, electrostatic interactions of clusters of positively charged amino acid residues with negatively charged lipids play an important role. Clusters of charged residues are often found in intrinsically disordered protein regions, which are highly abundant in the vicinity of the membrane forming what has been called the disordered boundary of the cell. Beyond contributing to the stability of the lipid-bound state, the pattern of charged residues may encode specific interactions or properties that form the basis of cell signaling. The element of this code may include, among others, the recognition, clustering, and selective release of phosphatidyl inositides, lipid-mediated protein-protein interactions changing the residence time of the peripheral membrane proteins or driving their approximation to integral membrane proteins. Boundary effects include reduction of dimensionality, protein reorientation, biassing of the conformational ensemble of disordered regions or enhanced 2D diffusion in the peri-membrane region enabled by the fuzzy character of the electrostatic interactions with an extended lipid membrane.

scholarly journals Circular dichroism spectroscopy of membrane proteins

2016 ◽  
Vol 45 (18) ◽  
pp. 4859-4872 ◽  
Author(s):  
A. J. Miles ◽  
B. A. Wallace
Keyword(s):  
Circular Dichroism ◽  
Membrane Proteins ◽  
Circular Dichroism Spectroscopy ◽  
Circular Dichroism Spectra ◽  
Helical Bundle ◽  
Beta Barrel ◽  
Circular Dichroïsm

Circular dichroism spectra of helical bundle (red), beta barrel (blue), and mixed helical/sheet/unordered (green) membrane proteins.

Solid state NMR of membrane proteins: methods and applications

2021 ◽  
Author(s):  
Vivien Yeh ◽  
Boyan B. Bonev
Keyword(s):  
Solid State ◽  
High Resolution ◽  
Membrane Proteins ◽  
Solid State Nmr ◽  
Lipid Membrane ◽  
Cell Function ◽  
Membrane Lipid ◽  
Pharmacological Intervention ◽  
Nmr Methods ◽  
Informative Approach

Membranes of cells are active barriers, in which membrane proteins perform essential remodelling, transport and recognition functions that are vital to cells. Membrane proteins are key regulatory components of cells and represent essential targets for the modulation of cell function and pharmacological intervention. However, novel folds, low molarity and the need for lipid membrane support present serious challenges to the characterisation of their structure and interactions. We describe the use of solid state NMR as a versatile and informative approach for membrane and membrane protein studies, which uniquely provides information on structure, interactions and dynamics of membrane proteins. High resolution approaches are discussed in conjunction with applications of NMR methods to studies of membrane lipid and protein structure and interactions. Signal enhancement in high resolution NMR spectra through DNP is discussed as a tool for whole cell and interaction studies.

Inter-residue interactions in alpha-helical transmembrane proteins

2018 ◽  
Vol 35 (15) ◽  
pp. 2578-2584 ◽  
Author(s):  
Eduardo Mayol ◽  
Mercedes Campillo ◽  
Arnau Cordomí ◽  
Mireia Olivella
Keyword(s):  
Membrane Proteins ◽  
Present Report ◽  
Protein Structures ◽  
Transmembrane Proteins ◽  
Globular Proteins ◽  
Supplementary Information ◽  
Backbone Carbonyl ◽  
Composition Characteristic ◽  
Almost All ◽  
Residue Composition

Abstract Motivation The number of available membrane protein structures has markedly increased in the last years and, in parallel, the reliability of the methods to detect transmembrane (TM) segments. In the present report, we characterized inter-residue interactions in α-helical membrane proteins using a dataset of 3462 TM helices from 430 proteins. This is by far the largest analysis published to date. Results Our analysis of residue–residue interactions in TM segments of membrane proteins shows that almost all interactions involve aliphatic residues and Phe. There is lack of polar–polar, polar–charged and charged–charged interactions except for those between Thr or Ser sidechains and the backbone carbonyl of aliphatic and Phe residues. The results are discussed in the context of the preferences of amino acids to be in the protein core or exposed to the lipid bilayer and to occupy specific positions along the TM segment. Comparison to datasets of β-barrel membrane proteins and of α-helical globular proteins unveils the specific patterns of interactions and residue composition characteristic of α-helical membrane proteins that are the clue to understanding their structure. Availability and implementation Results data and datasets used are available at http://lmc.uab.cat/TMalphaDB/interactions.php. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals The interplay between lipids and dopamine on α-synuclein oligomerization and membrane binding

2013 ◽  
Vol 33 (5) ◽  
Author(s):  
Chi L. L. Pham ◽  
Roberto Cappai
Keyword(s):  
Lipid Membranes ◽  
Amyloid Fibrils ◽  
Lipid Membrane ◽  
Hydrophobic Interactions ◽  
Membrane Integrity ◽  
Lipid Vesicles ◽  
Helical Conformation ◽  
Unfolded Protein ◽  
Natively Unfolded Protein ◽  
Natively Unfolded

The deposition of α-syn (α-synuclein) as amyloid fibrils and the selective loss of DA (dopamine) containing neurons in the substantia nigra are two key features of PD (Parkinson's disease). α-syn is a natively unfolded protein and adopts an α-helical conformation upon binding to lipid membrane. Oligomeric species of α-syn have been proposed to be the pathogenic species associated with PD because they can bind lipid membranes and disrupt membrane integrity. DA is readily oxidized to generate reactive intermediates and ROS (reactive oxygen species) and in the presence of DA, α-syn form of SDS-resistant soluble oligomers. It is postulated that the formation of the α-syn:DA oligomers involves the cross-linking of DA-melanin with α-syn, via covalent linkage, hydrogen and hydrophobic interactions. We investigate the effect of lipids on DA-induced α-syn oligomerization and studied the ability of α-syn:DA oligomers to interact with lipids vesicles. Our results show that the interaction of α-syn with lipids inhibits the formation of DA-induced α-syn oligomers. Moreover, the α-syn:DA oligomer cannot interact with lipid vesicles or cause membrane permeability. Thus, the formation of α-syn:DA oligomers may alter the actions of α-syn which require membrane association, leading to disruption of its normal cellular function.

scholarly journals The role of BamA in the biogenesis of beta-barrel membrane proteins

2014 ◽  
Vol 70 (a1) ◽  
pp. C578-C578
Author(s):  
Nicholas Noinaj ◽  
Adam Kuszak ◽  
Curtis Balusek ◽  
JC Gumbart ◽  
Petra Lukacik ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Outer Membrane ◽  
Crystal Structures ◽  
Outer Membrane Proteins ◽  
Hydrophobic Surface ◽  
Md Simulations ◽  
Structural Features ◽  
Bam Complex ◽  
Beta Barrel

Beta-barrel membrane proteins are essential for nutrient import, signaling, motility, and survival. In Gram-negative bacteria, the beta-barrel assembly machinery (BAM) complex is responsible for the biogenesis of beta-barrel outer membrane proteins (OMPs), with homologous complexes found in mitochondria and chloroplasts. Despite their essential roles, exactly how these OMPs are formed remains unknown. The BAM complex consists of a central and essential component called BamA (an OMP itself) and four lipoproteins called BamB-E. While the structure of the lipoproteins have been reported, the structure of full length BamA has been elusive. Recently though, we described the structure of BamA from two species of bacteria: Neisseria gonorrhoeae and Haemophilus ducreyi. BamA consists of a large periplasmic domain attached to a 16-strand transmembrane beta-barrel domain. Together, our crystal structures and molecule dynamics (MD) simulations revealed several structural features which gave clues to the mechanism by which BamA catalyzes beta-barrel assembly. The first is that the interior cavity is accessible in one BamA structure and conformationally closed in the other. Second, an exterior rim of the beta-barrel has a distinctly narrowed hydrophobic surface, locally destabilizing the outer membrane. Third, the beta-barrel can undergo lateral opening, suggesting a route from the interior cavity in BamA into the outer membrane. And fourth, a surface exposed exit pore positioned above the lateral opening site which may play a role in the biogenesis of extracellular loops. In this presentation, the crystal structures and MD simulations of BamA will be presented along with our work looking at the role of these four structural features in the role of BamA within the BAM complex.

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