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Current Biology : CB Apr 2018One-fourth of eukaryotic genes code for integral membrane proteins, nearly all of which are inserted and assembled at the endoplasmic reticulum (ER). The defining... (Review)
Review
One-fourth of eukaryotic genes code for integral membrane proteins, nearly all of which are inserted and assembled at the endoplasmic reticulum (ER). The defining feature of membrane proteins is one or more transmembrane domains (TMDs). During membrane protein biogenesis, TMDs are selectively recognized, shielded, and chaperoned into the lipid bilayer, where they often assemble with other TMDs. If maturation fails, exposed TMDs serve as a cue for engagement of degradation pathways. Thus, TMD-recognition factors in the cytosol and ER are essential for membrane protein biogenesis and quality control. Here, we discuss the growing assortment of cytosolic and membrane-embedded TMD-recognition factors, the pathways within which they operate, and mechanistic principles of recognition.
Topics: Animals; Cytosol; Endoplasmic Reticulum; Humans; Membrane Proteins; Molecular Chaperones; Protein Biosynthesis; Protein Domains; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 29689233
DOI: 10.1016/j.cub.2018.02.004 -
Biochimica Et Biophysica Acta Aug 2014Membrane protein folding and topogenesis are tuned to a given lipid profile since lipids and proteins have co-evolved to follow a set of interdependent rules governing... (Review)
Review
Membrane protein folding and topogenesis are tuned to a given lipid profile since lipids and proteins have co-evolved to follow a set of interdependent rules governing final protein topological organization. Transmembrane domain (TMD) topology is determined via a dynamic process in which topogenic signals in the nascent protein are recognized and interpreted initially by the translocon followed by a given lipid profile in accordance with the Positive Inside Rule. The net zero charged phospholipid phosphatidylethanolamine and other neutral lipids dampen the translocation potential of negatively charged residues in favor of the cytoplasmic retention potential of positively charged residues (Charge Balance Rule). This explains why positively charged residues are more potent topological signals than negatively charged residues. Dynamic changes in orientation of TMDs during or after membrane insertion are attributed to non-sequential cooperative and collective lipid-protein charge interactions as well as long-term interactions within a protein. The proportion of dual topological conformers of a membrane protein varies in a dose responsive manner with changes in the membrane lipid composition not only in vivo but also in vitro and therefore is determined by the membrane lipid composition. Switching between two opposite TMD topologies can occur in either direction in vivo and also in liposomes (designated as fliposomes) independent of any other cellular factors. Such lipid-dependent post-insertional reversibility of TMD orientation indicates a thermodynamically driven process that can occur at any time and in any cell membrane driven by changes in the lipid composition. This dynamic view of protein topological organization influenced by the lipid environment reveals previously unrecognized possibilities for cellular regulation and understanding of disease states resulting from mis-folded proteins. This article is part of a Special Issue entitled: Protein trafficking and secretion in bacteria. Guest Editors: Anastassios Economou and Ross Dalbey.
Topics: Bacteria; Cell Membrane; Cytoplasm; Lipids; Membrane Proteins; Phosphatidylethanolamines; Protein Folding; Protein Structure, Tertiary; Protein Transport
PubMed: 24341994
DOI: 10.1016/j.bbamcr.2013.12.007 -
FEBS Letters Aug 2014When taking up the gauntlet of studying membrane protein functionality, scientists are provided with a plethora of advantages, which can be exploited for the synthesis... (Review)
Review
When taking up the gauntlet of studying membrane protein functionality, scientists are provided with a plethora of advantages, which can be exploited for the synthesis of these difficult-to-express proteins by utilizing cell-free protein synthesis systems. Due to their hydrophobicity, membrane proteins have exceptional demands regarding their environment to ensure correct functionality. Thus, the challenge is to find the appropriate hydrophobic support that facilitates proper membrane protein folding. So far, various modes of membrane protein synthesis have been presented. Here, we summarize current state-of-the-art methodologies of membrane protein synthesis in biomimetic-supported systems. The correct folding and functionality of membrane proteins depend in many cases on their integration into a lipid bilayer and subsequent posttranslational modification. We highlight cell-free systems utilizing the advantages of biological membranes.
Topics: Animals; Biomimetic Materials; Cell Membrane; Cell-Free System; Humans; Membrane Proteins; Membranes, Artificial
PubMed: 24931371
DOI: 10.1016/j.febslet.2014.06.007 -
Biochimica Et Biophysica Acta Sep 2015We review the importance of helix motions for the function of several important categories of membrane proteins and for the properties of several model molecular... (Review)
Review
We review the importance of helix motions for the function of several important categories of membrane proteins and for the properties of several model molecular systems. For voltage-gated potassium or sodium channels, sliding, tilting and/or rotational movements of the S4 helix accompanied by a swapping of cognate side-chain ion-pair interactions regulate the channel gating. In the seven-helix G protein-coupled receptors, exemplified by the rhodopsins, collective helix motions serve to activate the functional signaling. Peptides which initially associate with lipid-bilayer membrane surfaces may undergo dynamic transitions from surface-bound to tilted-transmembrane orientations, sometimes accompanied by changes in the molecularity, formation of a pore or, more generally, the activation of biological function. For single-span membrane proteins, such as the tyrosine kinases, an interplay between juxtamembrane and transmembrane domains is likely to be crucial for the regulation of dimer assembly that in turn is associated with the functional responses to external signals. Additionally, we note that experiments with designed single-span transmembrane helices offer fundamental insights into the molecular features that govern protein-lipid interactions. This article is part of a Special Issue entitled: Lipid-protein interactions.
Topics: Animals; Humans; Kinetics; Lipid Bilayers; Membrane Lipids; Membrane Proteins; Models, Molecular; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary
PubMed: 25666872
DOI: 10.1016/j.bbamem.2015.01.019 -
BMC Biology Oct 2015Biological energy conversion in mitochondria is carried out by the membrane protein complexes of the respiratory chain and the mitochondrial ATP synthase in the inner... (Review)
Review
Biological energy conversion in mitochondria is carried out by the membrane protein complexes of the respiratory chain and the mitochondrial ATP synthase in the inner membrane cristae. Recent advances in electron cryomicroscopy have made possible new insights into the structural and functional arrangement of these complexes in the membrane, and how they change with age. This review places these advances in the context of what is already known, and discusses the fundamental questions that remain open but can now be approached.
Topics: Cellular Senescence; Cryoelectron Microscopy; Electron Transport; Membrane Proteins; Mitochondrial Membranes; Mitochondrial Proton-Translocating ATPases
PubMed: 26515107
DOI: 10.1186/s12915-015-0201-x -
Current Opinion in Structural Biology Aug 2015Membrane protein structural biology has benefitted tremendously from access to micro-focus crystallography at synchrotron radiation sources. X-ray free electron lasers... (Review)
Review
Membrane protein structural biology has benefitted tremendously from access to micro-focus crystallography at synchrotron radiation sources. X-ray free electron lasers (XFELs) are linear accelerator driven X-ray sources that deliver a jump in peak X-ray brilliance of nine orders of magnitude and represent a disruptive technology with potential to dramatically change the field. Membrane proteins were amongst the first macromolecules to be studied with XFEL radiation and include proof-of-principle demonstrations of serial femtosecond crystallography (SFX), the observation that XFEL data can deliver damage free crystallographic structures, initial experiments towards recording structural information from 2D arrays of membrane proteins, and time-resolved SFX, time-resolved wide angle X-ray scattering and time-resolved X-ray emission spectroscopy studies. Conversely, serial crystallography methods are now being applied using synchrotron radiation. We believe that a context dependent choice of synchrotron or XFEL radiation will accelerate progress towards novel insights in understanding membrane protein structure and dynamics.
Topics: Bacteria; Crystallography, X-Ray; Electrons; Humans; Lasers; Membrane Proteins; Molecular Biology; Nanoparticles; Protein Conformation; Spectrometry, X-Ray Emission; Synchrotrons
PubMed: 26342349
DOI: 10.1016/j.sbi.2015.08.006 -
The FEBS Journal Jun 2017The β-barrel assembly machinery (BAM) is a multicomponent complex responsible for the biogenesis of β-barrel outer membrane proteins (OMPs) in Gram-negative bacteria,... (Review)
Review
The β-barrel assembly machinery (BAM) is a multicomponent complex responsible for the biogenesis of β-barrel outer membrane proteins (OMPs) in Gram-negative bacteria, with conserved systems in both mitochondria and chloroplasts. Given its importance in the integrity of the outer membrane and in the assembly of surface exposed virulence factors, BAM is an attractive therapeutic target against pathogenic bacteria, particularly multidrug-resistant strains. While the mechanism for how BAM functions remains elusive, previous structural studies have described each of the individual components of BAM, offering only a few clues to how the complex functions. Recently, a number of structures have been reported of complexes, including that of fully assembled BAM in differing conformational states. These studies have provided the molecular blueprint detailing the atomic interactions between the components and have revealed new details about BAM, which suggest a dynamic mechanism that may use conformational changes to assist in the biogenesis of new OMPs.
Topics: Bacterial Outer Membrane Proteins; Gram-Negative Bacteria; Protein Structure, Secondary; Structure-Activity Relationship
PubMed: 27862971
DOI: 10.1111/febs.13960 -
Chemistry and Physics of Lipids Jan 2019The concept of a memtein as the minimal unit of membrane function is proposed here, and refers to the complex of a membrane protein together with a continuous layer of... (Review)
Review
The concept of a memtein as the minimal unit of membrane function is proposed here, and refers to the complex of a membrane protein together with a continuous layer of biological lipid molecules. The elucidation of the atomic resolution structures and specific interactions within memteins remains technically challenging. Nonetheless, we argue that these entities are critical endpoints for the postgenomic era, being essential units of cellular function that mediate signal transduction and trafficking. Their biological mechanisms and molecular compositions can be resolved using native nanodiscs formed by poly(styrene-co-maleic acid) (SMA) copolymers. These amphipathic polymers rapidly and spontaneously fragment membranes into water-soluble discs holding a section of bilayer. This allows structures of complexes found in vivo to be prepared without resorting to synthetic detergents or artificial lipids. The ex situ structures of memteins can be resolved by methods including cryo-electron microscopy (cEM), X-ray crystallography (XRC), NMR spectroscopy and mass spectrometry (MS). Progress in the field demonstrates that memteins are better representations of how biology actually works in membranes than naked proteins devoid of lipid, spurring on further advances in polymer chemistry to resolve their details.
Topics: Humans; Lipid Bilayers; Lipids; Membrane Proteins; Molecular Structure
PubMed: 30508515
DOI: 10.1016/j.chemphyslip.2018.11.008 -
The EMBO Journal Jan 2021The endoplasmic reticulum (ER) membrane protein complex (EMC) was identified over a decade ago in a genetic screen for ER protein homeostasis. The EMC inserts...
The endoplasmic reticulum (ER) membrane protein complex (EMC) was identified over a decade ago in a genetic screen for ER protein homeostasis. The EMC inserts transmembrane domains (TMDs) with limited hydrophobicity. Two recent cryo-EM structures, and a third model based on partial high- and low-resolution structures, suggest how this is accomplished.
Topics: Endoplasmic Reticulum; Humans; Intracellular Membranes; Membrane Proteins; Protein Biosynthesis; Protein Domains
PubMed: 33346928
DOI: 10.15252/embj.2020107407 -
Biochimica Et Biophysica Acta.... Apr 2018Recently, protein sequence coevolution analysis has matured into a predictive powerhouse for protein structure and function. Direct methods, which use global statistical... (Review)
Review
Recently, protein sequence coevolution analysis has matured into a predictive powerhouse for protein structure and function. Direct methods, which use global statistical models of sequence coevolution, have enabled the prediction of membrane and disordered protein structures, protein complex architectures, and the functional effects of mutations in proteins. The field of membrane protein biochemistry and structural biology has embraced these computational techniques, which provide functional and structural information in an otherwise experimentally-challenging field. Here we review recent applications of protein sequence coevolution analysis to membrane protein structure and function and highlight the promising directions and future obstacles in these fields. We provide insights and guidelines for membrane protein biochemists who wish to apply sequence coevolution analysis to a given experimental system.
Topics: Animals; Computational Biology; Evolution, Molecular; Humans; Membrane Proteins; Models, Molecular; Protein Binding; Protein Structure, Tertiary; Sequence Alignment
PubMed: 28993150
DOI: 10.1016/j.bbamem.2017.10.004