scholarly journals EncoMPASS: an Encyclopedia of Membrane Proteins Analyzed by Structure and Symmetry

2018 ◽  
Author(s):  
Antoniya A. Aleksandrova ◽  
Edoardo Sarti ◽  
Lucy R. Forrest
Keyword(s):  
Protein Structure ◽  
Membrane Proteins ◽  
Protein Function ◽  
Sequence Similarity ◽  
Protein Structure Determination ◽  
List Type ◽  
Online Tools ◽  
Structural Relationships ◽  
Step Procedure ◽  
Membrane Protein Function

SummaryProtein structure determination and prediction, active site detection, and protein sequence alignment techniques all exploit information about protein structure and structural relationships. For membrane proteins, however, there is no agreement among available online tools for highlighting and mapping such structural similarities. Moreover, no available resource provides a systematic overview of quaternary and internal symmetries, and their orientation with respect to the membrane, despite the fact that these properties can provide key insights into membrane protein function. To address these issues, we created theEncyclopediaofMembraneProteinsAnalyzed byStructure and Symmetry (EncoMPASS), a database for relating integral membrane proteins of known structure from the points of view of sequence, structure, and symmetry. EncoMPASS is accessible athttps://encompass.ninds.nih.govand its contents can be easily downloaded. This allows the user not only to focus on specific systems, but also to study general properties of the structure and evolution of membrane proteins.Highlights-EncoMPASS relates and analyzes known structures of membrane proteins-Structure and sequence similarity is assessed through alignments and topology considerations, not clustering-Symmetry is detected based on CE-Symm and SymD using a multi-step procedure

scholarly journals Structures of membrane proteins

2010 ◽  
Vol 43 (1) ◽  
pp. 65-158 ◽  
Author(s):  
Kutti R. Vinothkumar ◽  
Richard Henderson
Keyword(s):  
Protein Structure ◽  
Membrane Proteins ◽  
Membrane Protein ◽  
Protein Structures ◽  
Protein Structure Determination ◽  
Membrane Protein Structure ◽  
Expression Systems ◽  
Genome Sequences ◽  
Conformational Variability ◽  
Efficient Expression

AbstractIn reviewing the structures of membrane proteins determined up to the end of 2009, we present in words and pictures the most informative examples from each family. We group the structures together according to their function and architecture to provide an overview of the major principles and variations on the most common themes. The first structures, determined 20 years ago, were those of naturally abundant proteins with limited conformational variability, and each membrane protein structure determined was a major landmark. With the advent of complete genome sequences and efficient expression systems, there has been an explosion in the rate of membrane protein structure determination, with many classes represented. New structures are published every month and more than 150 unique membrane protein structures have been determined. This review analyses the reasons for this success, discusses the challenges that still lie ahead, and presents a concise summary of the key achievements with illustrated examples selected from each class.

scholarly journals Assessing the Role of Lipids in the Molecular Mechanism of Membrane Proteins

2021 ◽  
Vol 22 (14) ◽  
pp. 7267
Author(s):  
Léni Jodaitis ◽  
Thomas van Oene ◽  
Chloé Martens
Keyword(s):  
Membrane Proteins ◽  
Molecular Mechanism ◽  
Protein Interactions ◽  
Protein Function ◽  
Biological Membrane ◽  
Allosteric Coupling ◽  
Lipid Protein Interactions ◽  
Experimental Challenge ◽  
Membrane Protein Function

Membrane proteins have evolved to work optimally within the complex environment of the biological membrane. Consequently, interactions with surrounding lipids are part of their molecular mechanism. Yet, the identification of lipid–protein interactions and the assessment of their molecular role is an experimental challenge. Recently, biophysical approaches have emerged that are compatible with the study of membrane proteins in an environment closer to the biological membrane. These novel approaches revealed specific mechanisms of regulation of membrane protein function. Lipids have been shown to play a role in oligomerization, conformational transitions or allosteric coupling. In this review, we summarize the recent biophysical approaches, or combination thereof, that allow to decipher the role of lipid–protein interactions in the mechanism of membrane proteins.

Mechanisms underlying drug-mediated regulation of membrane protein function

2021 ◽  
Vol 118 (46) ◽  
pp. e2113229118
Author(s):  
Radda Rusinova ◽  
Changhao He ◽  
Olaf S. Andersen
Keyword(s):  
Membrane Proteins ◽  
Membrane Protein ◽  
Lipid Bilayer ◽  
Conformational Changes ◽  
Protein Function ◽  
Nonspecific Binding ◽  
Drug Induced ◽  
Protein Conformational Changes ◽  
Potassium Channel Kcsa ◽  
Membrane Protein Function

The hydrophobic coupling between membrane proteins and their host lipid bilayer provides a mechanism by which bilayer-modifying drugs may alter protein function. Drug regulation of membrane protein function thus may be mediated by both direct interactions with the protein and drug-induced alterations of bilayer properties, in which the latter will alter the energetics of protein conformational changes. To tease apart these mechanisms, we examine how the prototypical, proton-gated bacterial potassium channel KcsA is regulated by bilayer-modifying drugs using a fluorescence-based approach to quantify changes in both KcsA function and lipid bilayer properties (using gramicidin channels as probes). All tested drugs inhibited KcsA activity, and the changes in the different gating steps varied with bilayer thickness, suggesting a coupling to the bilayer. Examining the correlations between changes in KcsA gating steps and bilayer properties reveals that drug-induced regulation of membrane protein function indeed involves bilayer-mediated mechanisms. Both direct, either specific or nonspecific, binding and bilayer-mediated mechanisms therefore are likely to be important whenever there is overlap between the concentration ranges at which a drug alters membrane protein function and bilayer properties. Because changes in bilayer properties will impact many diverse membrane proteins, they may cause indiscriminate changes in protein function.

scholarly journals N-Glycosylation can selectively block or foster different receptor–ligand binding modes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Joni Vuorio ◽  
Jana Škerlová ◽  
Milan Fábry ◽  
Václav Veverka ◽  
Ilpo Vattulainen ◽  
...  
Keyword(s):  
Protein Structure ◽  
Binding Site ◽  
Protein Function ◽  
Protein Structure Determination ◽  
Host Protein ◽  
Cell Surface Receptor ◽  
Atomistic Simulations ◽  
Binding Modes ◽  
Surface Receptor ◽  
First Time

AbstractWhile DNA encodes protein structure, glycans provide a complementary layer of information to protein function. As a prime example of the significance of glycans, the ability of the cell surface receptor CD44 to bind its ligand, hyaluronan, is modulated by N-glycosylation. However, the details of this modulation remain unclear. Based on atomistic simulations and NMR, we provide evidence that CD44 has multiple distinct binding sites for hyaluronan, and that N-glycosylation modulates their respective roles. We find that non-glycosylated CD44 favors the canonical sub-micromolar binding site, while glycosylated CD44 binds hyaluronan with an entirely different micromolar binding site. Our findings show (for the first time) how glycosylation can alter receptor affinity by shielding specific regions of the host protein, thereby promoting weaker binding modes. The mechanism revealed in this work emphasizes the importance of glycosylation in protein function and poses a challenge for protein structure determination where glycosylation is usually neglected.

scholarly journals A general mechanism for drug promiscuity: Studies with amiodarone and other antiarrhythmics

2015 ◽  
Vol 146 (6) ◽  
pp. 463-475 ◽  
Author(s):  
Radda Rusinova ◽  
Roger E. Koeppe ◽  
Olaf S. Andersen
Keyword(s):  
Membrane Proteins ◽  
Lipid Bilayer ◽  
Protein Function ◽  
Single Channel ◽  
General Mechanism ◽  
Antiarrhythmic Agents ◽  
Diverse Range ◽  
Lipid Mixtures ◽  
Membrane Protein Function

Amiodarone is a widely prescribed antiarrhythmic drug used to treat the most prevalent type of arrhythmia, atrial fibrillation (AF). At therapeutic concentrations, amiodarone alters the function of many diverse membrane proteins, which results in complex therapeutic and toxicity profiles. Other antiarrhythmics, such as dronedarone, similarly alter the function of multiple membrane proteins, suggesting that a multipronged mechanism may be beneficial for treating AF, but raising questions about how these antiarrhythmics regulate a diverse range of membrane proteins at similar concentrations. One possible mechanism is that these molecules regulate membrane protein function by altering the common environment provided by the host lipid bilayer. We took advantage of the gramicidin (gA) channels’ sensitivity to changes in bilayer properties to determine whether commonly used antiarrhythmics—amiodarone, dronedarone, propranolol, and pindolol, whose pharmacological modes of action range from multi-target to specific—perturb lipid bilayer properties at therapeutic concentrations. Using a gA-based fluorescence assay, we found that amiodarone and dronedarone are potent bilayer modifiers at therapeutic concentrations; propranolol alters bilayer properties only at supratherapeutic concentration, and pindolol has little effect. Using single-channel electrophysiology, we found that amiodarone and dronedarone, but not propranolol or pindolol, increase bilayer elasticity. The overlap between therapeutic and bilayer-altering concentrations, which is observed also using plasma membrane–like lipid mixtures, underscores the need to explore the role of the bilayer in therapeutic as well as toxic effects of antiarrhythmic agents.

scholarly journals N-glycosylation blocks and simultaneously fosters different receptor-ligand binding sites: the chameleonic CD44–hyaluronan interaction

2020 ◽  
Author(s):  
Joni Vuorio ◽  
Jana Škerlová ◽  
Milan Fábry ◽  
Václav Veverka ◽  
Ilpo Vattulainen ◽  
...  
Keyword(s):  
Protein Structure ◽  
Binding Site ◽  
Binding Sites ◽  
Protein Function ◽  
Protein Structure Determination ◽  
Host Protein ◽  
Cell Surface Receptor ◽  
Binding Modes ◽  
Surface Receptor ◽  
First Time

ABSTRACTWhile DNA encodes protein structure, glycans provide a complementary layer of information to protein function. As a prime example of the significance of glycans, the ability of the cell surface receptor CD44 to bind its ligand, hyaluronan, is modulated by N-glycosylation. However, the details of this modulation remain unclear. Based on atomistic simulations and NMR, we provide evidence that CD44 has multiple distinct binding sites for hyaluronan, and that N-glycosylation modulates their respective roles. We find that non-glycosylated CD44 favors the canonical sub-micromolar binding site, while glycosylated CD44 binds hyaluronan with an entirely different micromolar binding site. Our findings show (for the first time) how glycosylation can alter receptor affinity by shielding specific regions of the host protein, thereby promoting weaker binding modes. The mechanism revealed in this work emphasizes the importance of glycosylation in protein function and poses a challenge for protein structure determination where glycosylation is usually neglected.

scholarly journals Lysine acetylation regulates the interaction between proteins and membranes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Alan K. Okada ◽  
Kazuki Teranishi ◽  
Mark R. Ambroso ◽  
Jose Mario Isas ◽  
Elena Vazquez-Sarandeses ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Membrane Protein ◽  
Protein Function ◽  
Genetic Manipulation ◽  
Membrane Binding ◽  
Fluorescent Imaging ◽  
Lysine Acetylation ◽  
Peripheral Membrane Proteins ◽  
Membrane Protein Function

AbstractLysine acetylation regulates the function of soluble proteins in vivo, yet it remains largely unexplored whether lysine acetylation regulates membrane protein function. Here, we use bioinformatics, biophysical analysis of recombinant proteins, live-cell fluorescent imaging and genetic manipulation of Drosophila to explore lysine acetylation in peripheral membrane proteins. Analysis of 50 peripheral membrane proteins harboring BAR, PX, C2, or EHD membrane-binding domains reveals that lysine acetylation predominates in membrane-interaction regions. Acetylation and acetylation-mimicking mutations in three test proteins, amphiphysin, EHD2, and synaptotagmin1, strongly reduce membrane binding affinity, attenuate membrane remodeling in vitro and alter subcellular localization. This effect is likely due to the loss of positive charge, which weakens interactions with negatively charged membranes. In Drosophila, acetylation-mimicking mutations of amphiphysin cause severe disruption of T-tubule organization and yield a flightless phenotype. Our data provide mechanistic insights into how lysine acetylation regulates membrane protein function, potentially impacting a plethora of membrane-related processes.

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