Mutations in transmembrane proteins: diseases, evolutionary insights, prediction and comparison with globular proteins

2020 ◽  
Author(s):  
Jan Zaucha ◽  
Michael Heinzinger ◽  
A Kulandaisamy ◽  
Evans Kataka ◽  
Óscar Llorian Salvádor ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Membrane Protein ◽  
Lipid Bilayers ◽  
Protein Structures ◽  
Experimental Studies ◽  
Single Amino Acid ◽  
Evolutionary Information ◽  
Missense Variants ◽  
Current State ◽  
Aqueous Environments

Abstract Membrane proteins are unique in that they interact with lipid bilayers, making them indispensable for transporting molecules and relaying signals between and across cells. Due to the significance of the protein’s functions, mutations often have profound effects on the fitness of the host. This is apparent both from experimental studies, which implicated numerous missense variants in diseases, as well as from evolutionary signals that allow elucidating the physicochemical constraints that intermembrane and aqueous environments bring. In this review, we report on the current state of knowledge acquired on missense variants (referred to as to single amino acid variants) affecting membrane proteins as well as the insights that can be extrapolated from data already available. This includes an overview of the annotations for membrane protein variants that have been collated within databases dedicated to the topic, bioinformatics approaches that leverage evolutionary information in order to shed light on previously uncharacterized membrane protein structures or interaction interfaces, tools for predicting the effects of mutations tailored specifically towards the characteristics of membrane proteins as well as two clinically relevant case studies explaining the implications of mutated membrane proteins in cancer and cardiomyopathy.

Self-assembling Peptide Detergent A6D Directly Associates with Bovine Rhodopsin and Forms Lipid-like Vesicles

2004 ◽  
Vol 845 ◽  
Author(s):  
Xiaojun Zhao ◽  
Yusuke Nagai ◽  
Shuguang Zhang
Keyword(s):  
Membrane Proteins ◽  
Membrane Protein ◽  
Lipid Bilayers ◽  
Self Assembly ◽  
Protein Structures ◽  
Detergent Solution ◽  
Self Assembling ◽  
Bovine Rhodopsin ◽  
Hydrophobic Tail ◽  
New Type

ABSTRACTMembrane protein study critically depends on detergents, which are amphilhilic molecules containing a hydrophilic “head” and a hydrophobic “tail” to mimic biological lipid bilayers to stabilize membrane proteins. However, detergents are not fully equivalent to lipid bilayers and in fact they only partly mimic lipid bilayers function. Consequently, membrane proteins in detergent solution are more or less denatured because detergents can not effectively stabilize membrane protein structures. Therefore, it is urgent to develop new types of detergents for more effectively stabilizing membrane proteins. Previously, we have reported a new type of self-assembly peptide detergents containing a hydrophilic head composed of either a negatively charged aspartic acid or a positively charged lysine and a tail of hydrophobic amino acids of six connective alanines. This new peptide detergent has been shown to be more effective for protecting membrane protein PS I structure than that the conventional detergent does. However, what type of physical structures peptide detergent can form is unclear yet. Here we presented our AFM and DSL analysis of the peptide detergent A6D, which not only form mixed micelles with n-Octyl-beta-D-Glucoside (OG) to solubilize membrane protein rhodopsin, but also can mimic lipid bilayers to keep rhodopsin in lipid-like vesicles for its structure preservation.

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 Mutations of the YidC Insertase alleviate stress from σM-dependent membrane protein overproduction in Bacillus subtilis

2019 ◽  
Author(s):  
Heng Zhao ◽  
Ankita J. Sachla ◽  
John D. Helmann
Keyword(s):  
Oxidative Stress ◽  
Cell Wall ◽  
Bacillus Subtilis ◽  
Membrane Proteins ◽  
Membrane Protein ◽  
Substrate Binding ◽  
Single Amino Acid ◽  
Cell Wall Synthesis ◽  
Intrinsic Resistance ◽  
Σ Factor

AbstractIn Bacillus subtilis, the extracytoplasmic function σ factor σM regulates cell wall synthesis and is critical for intrinsic resistance to cell wall targeting antibiotics. The anti-σ factors YhdL and YhdK form a complex that restricts the basal activity of σM, and the absence of YhdL leads to runaway expression of the σM regulon and cell death. Here, we report that this lethality can be suppressed by gain-of-function mutations in spoIIIJ, which encodes the major YidC membrane protein insertase in B. subtilis. B. subtilis PY79 SpoIIIJ contains a single amino acid substitution in the substrate-binding channel (Q140K), and this allele suppresses the lethality of high SigM. Analysis of a library of YidC variants reveals that increased charge (+2 or +3) in the substrate-binding channel can compensate for high expression of the σM regulon. Derepression of the σM regulon induces secretion stress, oxidative stress and DNA damage responses, all of which can be alleviated by the YidCQ140K substitution. We further show that the fitness defect caused by high σM activity is exacerbated in the absence of SecDF protein translocase or σM-dependent induction of the Spx oxidative stress regulon. Conversely, cell growth is improved by mutation of specific σM-dependent promoters controlling operons encoding integral membrane proteins. Collectively, these results reveal how the σM regulon has evolved to up-regulate membrane-localized complexes involved in cell wall synthesis, and to simultaneously counter the resulting stresses imposed by regulon induction.Author SummaryBacteria frequently produce antibiotics that inhibit the growth of competitors, and many naturally occurring antibiotics target cell wall synthesis. In Bacillus subtilis, the alternative σ factor σM is induced by cell wall antibiotics, and upregulates genes for peptidoglycan and cell envelope synthesis. However, dysregulation of the σM regulon, resulting from loss of the YhdL anti-σM protein, is lethal. We here identify charge variants of the SpoIIIJ(YidC) membrane protein insertase that suppress the lethal effects of high σM activity. Further analyses reveal that induction of the σM regulon leads to high level expression of membrane proteins that trigger envelope stress, and this stress is countered by specific genes in the σM regulon.

scholarly journals Evidence for Membrane Complex Assembly in Nanoelectrospray Generated Lipid Bilayers

2019 ◽  
Author(s):  
Matthias Wilm
Keyword(s):  
Membrane Proteins ◽  
Membrane Protein ◽  
Lipid Bilayers ◽  
Layered Structure ◽  
Protein Complexes ◽  
Complex Assembly ◽  
Membrane Complex ◽  
Detergent Extraction ◽  
Membrane Protein Complexes

1.AbstractNanoelectrospray can be used to generate a layered structure consisting of bipolar lipids, detergent-solubilized membrane proteins, and glycerol that self-assembles upon detergent extraction into one extended layer of a protein containing membrane. This manuscript presents the first evidence that this method might allow membrane protein complexes to assemble in this process.

scholarly journals Methods for the solubilisation of membrane proteins: the micelle-aneous world of membrane protein solubilisation

2021 ◽  
Author(s):  
Giedre Ratkeviciute ◽  
Benjamin F. Cooper ◽  
Timothy J. Knowles
Keyword(s):  
Membrane Proteins ◽  
Membrane Protein ◽  
Protein Stability ◽  
Lipid Membranes ◽  
Lipid Membrane ◽  
Modus Operandi ◽  
Membrane Mimetic ◽  
Aqueous Environments ◽  
Recent Developments

The solubilisation of membrane proteins (MPs) necessitates the overlap of two contradictory events; the extraction of MPs from their native lipid membranes and their subsequent stabilisation in aqueous environments. Whilst the current myriad of membrane mimetic systems provide a range of modus operandi, there are no golden rules for selecting the optimal pipeline for solubilisation of a specific MP hence a miscellaneous approach must be employed balancing both solubilisation efficiency and protein stability. In recent years, numerous diverse lipid membrane mimetic systems have been developed, expanding the pool of available solubilisation strategies. This review provides an overview of recent developments in the membrane mimetic field, with particular emphasis placed upon detergents, polymer-based nanodiscs and amphipols, highlighting the latest reagents to enter the toolbox of MP research.

scholarly journals BRANEart: identify stability strength and weakness regions in membrane proteins

2021 ◽  
Author(s):  
Sankar Basu ◽  
Simon S. Assaf ◽  
Fabian Teheux ◽  
Marianne Rooman ◽  
Fabrizio Pucci
Keyword(s):  
Membrane Proteins ◽  
Membrane Protein ◽  
Conformational Changes ◽  
Large Scale ◽  
Protein Structures ◽  
Accurate Method ◽  
Globular Proteins ◽  
Stability Properties ◽  
Overall Stability ◽  
The Stability

AbstractUnderstanding the role of stability strengths and weaknesses in proteins is a key objective for rationalizing their dynamical and functional properties such as conformational changes, catalytic activity, and protein-protein and protein-ligand interactions. We present BRANEart, a new, fast and accurate method to evaluate the per-residue contributions to the overall stability of membrane proteins. It is based on an extended set of recently introduced statistical potentials derived from membrane protein structures, which better describe the stability properties of this class of proteins than standard potentials derived from globular proteins. We defined a per-residue membrane propensity index from combinations of these potentials, which can be used to identify residues which strongly contribute to the stability of the transmembrane region or which would, on the contrary, be more stable in extramembrane regions, or vice versa. Large-scale application to membrane and globular proteins sets and application to tests cases show excellent agreement with experimental data. BRANEart thus appears as a useful instrument to analyze in detail the overall stability properties of a target membrane protein, to position it relative to the lipid bilayer, and to rationally modify its biophysical characteristics and function. BRANEart can be freely accessed from http://babylone.3bio.ulb.ac.be/BRANEart.

scholarly journals Tryptophan, an Amino-Acid Endowed with Unique Properties and Its Many Roles in Membrane Proteins

Crystals ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1032
Author(s):  
Sonia Khemaissa ◽  
Sandrine Sagan ◽  
Astrid Walrant
Keyword(s):  
Amino Acid ◽  
Membrane Proteins ◽  
Hydrogen Bonds ◽  
Membrane Protein ◽  
Lipid Bilayers ◽  
Noncovalent Interactions ◽  
Chemical Properties ◽  
Protein Stabilization ◽  
Physico Chemical

Tryptophan is an aromatic amino acid with unique physico-chemical properties. It is often encountered in membrane proteins, especially at the level of the water/bilayer interface. It plays a role in membrane protein stabilization, anchoring and orientation in lipid bilayers. It has a hydrophobic character but can also engage in many types of interactions, such as π–cation or hydrogen bonds. In this review, we give an overview of the role of tryptophan in membrane proteins and a more detailed description of the underlying noncovalent interactions it can engage in with membrane partners.

scholarly journals Membrane Protein Structures in Lipid Bilayers; Small-Angle Neutron Scattering With Contrast-Matched Bicontinuous Cubic Phases

2021 ◽  
Vol 8 ◽  
Author(s):  
Charlotte E. Conn ◽  
Liliana de Campo ◽  
Andrew E. Whitten ◽  
Christopher J. Garvey ◽  
Anwen M. Krause-Heuer ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Neutron Scattering ◽  
Phase Behavior ◽  
Lipid Bilayers ◽  
Small Angle ◽  
Small Angle Neutron Scattering ◽  
Protein Structures ◽  
Bicontinuous Cubic ◽  
Contrast Matching ◽  
Detergent Micelles

This perspective describes advances in determining membrane protein structures in lipid bilayers using small-angle neutron scattering (SANS). Differentially labeled detergents with a homogeneous scattering length density facilitate contrast matching of detergent micelles; this has previously been used successfully to obtain the structures of membrane proteins. However, detergent micelles do not mimic the lipid bilayer environment of the cell membrane in vivo. Deuterated vesicles can be used to obtain the radius of gyration of membrane proteins, but protein-protein interference effects within the vesicles severely limits this method such that the protein structure cannot be modeled. We show herein that different membrane protein conformations can be distinguished within the lipid bilayer of the bicontinuous cubic phase using contrast-matching. Time-resolved studies performed using SANS illustrate the complex phase behavior in lyotropic liquid crystalline systems and emphasize the importance of this development. We believe that studying membrane protein structures and phase behavior in contrast-matched lipid bilayers will advance both biological and pharmaceutical applications of membrane-associated proteins, biosensors and food science.

scholarly journals Lipid binding attenuates channel closure of the outer membrane protein OmpF

2018 ◽  
Vol 115 (26) ◽  
pp. 6691-6696 ◽  
Author(s):  
Idlir Liko ◽  
Matteo T. Degiacomi ◽  
Sejeong Lee ◽  
Thomas D. Newport ◽  
Joseph Gault ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Membrane Protein ◽  
Outer Membrane ◽  
Lipid Bilayers ◽  
Protein Structures ◽  
Anion Channel ◽  
Lipid Binding ◽  
Coarse Grained ◽  
Strong Interactions ◽  
Voltage Dependent Anion Channel

Strong interactions between lipids and proteins occur primarily through association of charged headgroups and amino acid side chains, rendering the protonation status of both partners important. Here we use native mass spectrometry to explore lipid binding as a function of charge of the outer membrane porin F (OmpF). We find that binding of anionic phosphatidylglycerol (POPG) or zwitterionic phosphatidylcholine (POPC) to OmpF is sensitive to electrospray polarity while the effects of charge are less pronounced for other proteins in outer or mitochondrial membranes: the ferripyoverdine receptor (FpvA) or the voltage-dependent anion channel (VDAC). Only marginal charge-induced differences were observed for inner membrane proteins: the ammonia channel (AmtB) or the mechanosensitive channel. To understand these different sensitivities, we performed an extensive bioinformatics analysis of membrane protein structures and found that OmpF, and to a lesser extent FpvA and VDAC, have atypically high local densities of basic and acidic residues in their lipid headgroup-binding regions. Coarse-grained molecular dynamics simulations, in mixed lipid bilayers, further implicate changes in charge by demonstrating preferential binding of anionic POPG over zwitterionic POPC to protonated OmpF, an effect not observed to the same extent for AmtB. Moreover, electrophysiology and mass-spectrometry–based ligand-binding experiments, at low pH, show that POPG can maintain OmpF channels in open conformations for extended time periods. Since the outer membrane is composed almost entirely of anionic lipopolysaccharide, with similar headgroup properties to POPG, such anionic lipid binding could prevent closure of OmpF channels, thereby increasing access of antibiotics that use porin-mediated pathways.

scholarly journals Membrane protein engineering to the rescue

2018 ◽  
Vol 46 (6) ◽  
pp. 1541-1549
Author(s):  
Andrea E. Rawlings
Keyword(s):  
Membrane Proteins ◽  
Membrane Protein ◽  
Protein Engineering ◽  
Mutation Screening ◽  
Water Soluble ◽  
Scaffold Proteins ◽  
Major Barrier ◽  
Expression Levels ◽  
Aqueous Environments ◽  
Protein Research

The inherent hydrophobicity of membrane proteins is a major barrier to membrane protein research and understanding. Their low stability and solubility in aqueous environments coupled with poor expression levels make them a challenging area of research. For many years, the only way of working with membrane proteins was to optimise the environment to suit the protein, through the use of different detergents, solubilising additives, and other adaptations. However, with innovative protein engineering methodologies, the membrane proteins themselves are now being adapted to suit the environment. This mini-review looks at the types of adaptations which are applied to membrane proteins from a variety of different fields, including water solubilising fusion tags, thermostabilising mutation screening, scaffold proteins, stabilising protein chimeras, and isolating water-soluble domains.

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