scholarly journals Discovery of novel membrane binding structures and functions

2014 ◽  
Vol 92 (6) ◽  
pp. 555-563 ◽  
Author(s):  
Irina Kufareva ◽  
Marc Lenoir ◽  
Felician Dancea ◽  
Pooja Sridhar ◽  
Eugene Raush ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Lipid Bilayers ◽  
Protein Interactions ◽  
Membrane Binding ◽  
Three Dimensional ◽  
Intrinsic Activity ◽  
Resonance Spectroscopy ◽  
Pleckstrin Homology ◽  
Lysobisphosphatidic Acid ◽  
Membrane Interactive

The function of a protein is determined by its intrinsic activity in the context of its subcellular distribution. Membranes localize proteins within cellular compartments and govern their specific activities. Discovering such membrane-protein interactions is important for understanding biological mechanisms and could uncover novel sites for therapeutic intervention. We present a method for detecting membrane interactive proteins and their exposed residues that insert into lipid bilayers. Although the development process involved analysis of how C1b, C2, ENTH, FYVE, Gla, pleckstrin homology (PH), and PX domains bind membranes, the resulting membrane optimal docking area (MODA) method yields predictions for a given protein of known three-dimensional structures without referring to canonical membrane-targeting modules. This approach was tested on the Arf1 GTPase, ATF2 acetyltransferase, von Willebrand factor A3 domain, and Neisseria gonorrhoeae MsrB protein and further refined with membrane interactive and non-interactive FAPP1 and PKD1 pleckstrin homology domains, respectively. Furthermore we demonstrate how this tool can be used to discover unprecedented membrane binding functions as illustrated by the Bro1 domain of Alix, which was revealed to recognize lysobisphosphatidic acid (LBPA). Validation of novel membrane-protein interactions relies on other techniques such as nuclear magnetic resonance spectroscopy (NMR), which was used here to map the sites of micelle interaction. Together this indicates that genome-wide identification of known and novel membrane interactive proteins and sites is now feasible and provides a new tool for functional annotation of the proteome.

scholarly journals Lipid bilayer induces contraction of the denatured state ensemble of a helical-bundle membrane protein

2021 ◽  
Vol 119 (1) ◽  
pp. e2109169119
Author(s):  
Kristen A. Gaffney ◽  
Ruiqiong Guo ◽  
Michael D. Bridges ◽  
Shaima Muhammednazaar ◽  
Daoyang Chen ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Lipid Bilayer ◽  
Lipid Bilayers ◽  
Limited Proteolysis ◽  
Water Soluble ◽  
Disordered Proteins ◽  
Resonance Spectroscopy ◽  
Denatured State ◽  
E Coli ◽  
State Ensemble

Defining the denatured state ensemble (DSE) and disordered proteins is essential to understanding folding, chaperone action, degradation, and translocation. As compared with water-soluble proteins, the DSE of membrane proteins is much less characterized. Here, we measure the DSE of the helical membrane protein GlpG of Escherichia coli (E. coli) in native-like lipid bilayers. The DSE was obtained using our steric trapping method, which couples denaturation of doubly biotinylated GlpG to binding of two streptavidin molecules. The helices and loops are probed using limited proteolysis and mass spectrometry, while the dimensions are determined using our paramagnetic biotin derivative and double electron–electron resonance spectroscopy. These data, along with our Upside simulations, identify the DSE as being highly dynamic, involving the topology changes and unfolding of some of the transmembrane (TM) helices. The DSE is expanded relative to the native state but only to 15 to 75% of the fully expanded condition. The degree of expansion depends on the local protein packing and the lipid composition. E. coli’s lipid bilayer promotes the association of TM helices in the DSE and, probably in general, facilitates interhelical interactions. This tendency may be the outcome of a general lipophobic effect of proteins within the cell membranes.

scholarly journals Structural Features of Tight-Junction Proteins

2019 ◽  
Vol 20 (23) ◽  
pp. 6020 ◽  
Author(s):  
Udo Heinemann ◽  
Anja Schuetz
Keyword(s):  
Tight Junction ◽  
Tight Junctions ◽  
Protein Interactions ◽  
Three Dimensional ◽  
Structural Features ◽  
Resonance Spectroscopy ◽  
Tight Junction Proteins ◽  
Protein Protein Interactions ◽  
X Ray Crystallography ◽  
Junction Proteins

Tight junctions are complex supramolecular entities composed of integral membrane proteins, membrane-associated and soluble cytoplasmic proteins engaging in an intricate and dynamic system of protein–protein interactions. Three-dimensional structures of several tight-junction proteins or their isolated domains have been determined by X-ray crystallography, nuclear magnetic resonance spectroscopy, and cryo-electron microscopy. These structures provide direct insight into molecular interactions that contribute to the formation, integrity, or function of tight junctions. In addition, the known experimental structures have allowed the modeling of ligand-binding events involving tight-junction proteins. Here, we review the published structures of tight-junction proteins. We show that these proteins are composed of a limited set of structural motifs and highlight common types of interactions between tight-junction proteins and their ligands involving these motifs.

Membrane Protein–Lipid Interactions Probed Using Mass Spectrometry

2019 ◽  
Vol 88 (1) ◽  
pp. 85-111 ◽  
Author(s):  
Jani Reddy Bolla ◽  
Mark T. Agasid ◽  
Shahid Mehmood ◽  
Carol V. Robinson
Keyword(s):  
Mass Spectrometry ◽  
Membrane Protein ◽  
Lipid Bilayers ◽  
Protein Interactions ◽  
Native Mass Spectrometry ◽  
Lipid Interactions ◽  
X Ray Crystallography ◽  
Native Ms ◽  
Molecular Aspects ◽  
Lipid Protein Interactions

Membrane proteins that exist in lipid bilayers are not isolated molecular entities. The lipid molecules that surround them play crucial roles in maintaining their full structural and functional integrity. Research directed at investigating these critical lipid–protein interactions is developing rapidly. Advancements in both instrumentation and software, as well as in key biophysical and biochemical techniques, are accelerating the field. In this review, we provide a brief outline of structural techniques used to probe protein–lipid interactions and focus on the molecular aspects of these interactions obtained from native mass spectrometry (native MS). We highlight examples in which lipids have been shown to modulate membrane protein structure and show how native MS has emerged as a complementary technique to X-ray crystallography and cryo–electron microscopy. We conclude with a short perspective on future developments that aim to better understand protein–lipid interactions in the native environment.

scholarly journals Membrane-Protein Interactions in a Generic Coarse-Grained Model for Lipid Bilayers

2009 ◽  
Vol 96 (1) ◽  
pp. 101-115 ◽  
Author(s):  
Beate West ◽  
Frank L.H. Brown ◽  
Friederike Schmid
Keyword(s):  
Membrane Protein ◽  
Lipid Bilayers ◽  
Protein Interactions ◽  
Coarse Grained ◽  
Coarse Grained Model

scholarly journals Unraveling membrane properties at the organelle-level with LipidDyn

2022 ◽  
Author(s):  
Simone Scrima ◽  
Matteo Tiberti ◽  
Alessia Campo ◽  
Elisabeth Corcelle-Termeau ◽  
Delphine Judith ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Lipid Bilayers ◽  
Protein Interactions ◽  
Transmembrane Protein ◽  
Md Simulations ◽  
Membrane Properties ◽  
Cellular Membranes ◽  
Simulation Data ◽  
Membrane Function ◽  
Cellular Environment

Cellular membranes are formed from many different lipids in various amounts and proportions depending on the subcellular localization. The lipid composition of membranes is sensitive to changes in the cellular environment, and their alterations are linked to several diseases, including cancer. Lipids not only form lipid-lipid interactions but also interact with other biomolecules, including proteins, profoundly impacting each other. Molecular dynamics (MD) simulations are a powerful tool to study the properties of cellular membranes and membrane-protein interactions on different timescales and at varying levels of resolution. Over the last few years, software and hardware for biomolecular simulations have been optimized to routinely run long simulations of large and complex biological systems. On the other hand, high-throughput techniques based on lipidomics provide accurate estimates of the composition of cellular membranes at the level of subcellular compartments. The community needs computational tools for lipidomics and simulation data effectively interacting to better understand how changes in lipid compositions impact membrane function and structure. Lipidomic data can be analyzed to design biologically relevant models of membranes for MD simulations. Similar applications easily result in a massive amount of simulation data where the bottleneck becomes the analysis of the data to understand how membrane properties and membrane-protein interactions are changing in the different conditions. In this context, we developed LipidDyn, an in silico pipeline to streamline the analyses of MD simulations of membranes of different compositions. Once the simulations are collected, LipidDyn provides average properties and time series for several membrane properties such as area per lipid, thickness, diffusion motions, the density of lipid bilayers, and lipid enrichment/depletion. The calculations exploit parallelization and the pipelines include graphical outputs in a publication-ready form. We applied LipidDyn to different case studies to illustrate its potential, including membranes from cellular compartments and transmembrane protein domains. LipidDyn is implemented in Python and relies on open-source libraries. LipidDyn is available free of charge under the GNU General Public License from https://github.com/ELELAB/LipidDyn.

An Update on Recent Advances in Cubosome: A Novel Drug Delivery System

2021 ◽  
Vol 21 ◽  
Author(s):  
Madhukar Garg ◽  
Anju Goyal ◽  
Sapna Kumari
Keyword(s):  
Drug Delivery ◽  
Drug Delivery System ◽  
Lipid Bilayers ◽  
Delivery System ◽  
Liquid Crystalline ◽  
Three Dimensional ◽  
Biologically Active ◽  
Potential Applications ◽  
Health Related ◽  
Novel Drug

: Cubosomes are highly stable nanostructured liquid crystalline dosage delivery form derived from amphiphilic lipids and polymer-based stabilizers converting it in a form of effective biocompatible carrier for the drug delivery. The delivery form comprised of bicontinuous lipid bilayers arranged in three dimensional honeycombs like structure provided with two internal aqueous channels for incorporation of number of biologically active ingredients. In contrast liposomes they provide large surface area for incorporation of different types of ingredients. Due to the distinct advantages of biocompatibility and thermodynamic stability, cubosomes have remained the first preference as method of choice in the sustained release, controlled release and targeted release dosage forms as new drug delivery system for the better release of the drugs. As lot of advancement in the new form of dosage form has bring the novel avenues in drug delivery mechanisms so it was matter of worth to compile the latest updates on the various aspects of mentioned therapeutic delivery system including its structure, routes of applications along with the potential applications to encapsulate variety drugs to serve health related benefits.

scholarly journals Structural Characterization of Receptor–Receptor Interactions in the Allosteric Modulation of G Protein-Coupled Receptor (GPCR) Dimers

2021 ◽  
Vol 22 (6) ◽  
pp. 3241
Author(s):  
Raudah Lazim ◽  
Donghyuk Suh ◽  
Jai Woo Lee ◽  
Thi Ngoc Lan Vu ◽  
Sanghee Yoon ◽  
...  
Keyword(s):  
G Protein ◽  
Protein Interactions ◽  
Metabotropic Glutamate Receptor ◽  
Three Dimensional ◽  
Allosteric Modulation ◽  
Experimental Investigations ◽  
G Protein Coupled Receptor ◽  
Metabotropic Glutamate ◽  
Gpcr Activation ◽  
G Protein Coupled

G protein-coupled receptor (GPCR) oligomerization, while contentious, continues to attract the attention of researchers. Numerous experimental investigations have validated the presence of GPCR dimers, and the relevance of dimerization in the effectuation of physiological functions intensifies the attractiveness of this concept as a potential therapeutic target. GPCRs, as a single entity, have been the main source of scrutiny for drug design objectives for multiple diseases such as cancer, inflammation, cardiac, and respiratory diseases. The existence of dimers broadens the research scope of GPCR functions, revealing new signaling pathways that can be targeted for disease pathogenesis that have not previously been reported when GPCRs were only viewed in their monomeric form. This review will highlight several aspects of GPCR dimerization, which include a summary of the structural elucidation of the allosteric modulation of class C GPCR activation offered through recent solutions to the three-dimensional, full-length structures of metabotropic glutamate receptor and γ-aminobutyric acid B receptor as well as the role of dimerization in the modification of GPCR function and allostery. With the growing influence of computational methods in the study of GPCRs, we will also be reviewing recent computational tools that have been utilized to map protein–protein interactions (PPI).

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