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Cellular and Molecular Life Sciences :... Sep 2017Intrinsic disorder is common in integral membrane proteins, particularly in the intracellular domains. Despite this observation, these domains are not always recognized... (Review)
Review
Intrinsic disorder is common in integral membrane proteins, particularly in the intracellular domains. Despite this observation, these domains are not always recognized as being disordered. In this review, we will discuss the biological functions of intrinsically disordered regions of membrane proteins, and address why the flexibility afforded by disorder is mechanistically important. Intrinsically disordered regions are present in many common classes of membrane proteins including ion channels and transporters; G-protein coupled receptors (GPCRs), receptor tyrosine kinases and cytokine receptors. The functions of the disordered regions are many and varied. We will discuss selected examples including: (1) Organization of receptors, kinases, phosphatases and second messenger sources into signaling complexes. (2) Modulation of the membrane-embedded domain function by ball-and-chain like mechanisms. (3) Trafficking of membrane proteins. (4) Transient membrane associations. (5) Post-translational modifications most notably phosphorylation and (6) disorder-linked isoform dependent function. We finish the review by discussing the future challenges facing the membrane protein community regarding protein disorder.
Topics: Cell Membrane; Humans; Intrinsically Disordered Proteins; Membrane Proteins; Protein Isoforms; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 28601983
DOI: 10.1007/s00018-017-2562-5 -
Protein Science : a Publication of the... Mar 2019Transmembrane electrostatic membrane potential is a major energy source of the cell. Importantly, it determines the structure as well as function of charge-carrying... (Review)
Review
Transmembrane electrostatic membrane potential is a major energy source of the cell. Importantly, it determines the structure as well as function of charge-carrying membrane proteins. Here, we discuss the relationship between membrane potential and membrane proteins, in particular whether the conformation of these proteins is integrally connected to the membrane potential. Together, these concepts provide a framework for rationalizing the types of conformational changes that have been observed in membrane proteins and for better understanding the electrostatic effects of the membrane potential on both reversible as well as unidirectional dynamic processes of membrane proteins.
Topics: Animals; Cell Membrane; Humans; Membrane Potentials; Membrane Proteins; Molecular Dynamics Simulation; Protein Conformation; Static Electricity
PubMed: 30549351
DOI: 10.1002/pro.3563 -
Biochimica Et Biophysica Acta.... May 2018Membrane proteins play important roles in cell survival and cell communication, as they function as transporters, receptors, anchors and enzymes. They are also potential... (Review)
Review
BACKGROUND
Membrane proteins play important roles in cell survival and cell communication, as they function as transporters, receptors, anchors and enzymes. They are also potential targets for drugs that block receptors or inhibit enzymes related to diseases. Although the number of known structures of membrane proteins is still small relative to the size of the proteome as a whole, many new membrane protein structures have been determined recently.
SCOPE OF THE ARTICLE
We compared and analyzed the widely used membrane protein databases, mpstruc, Orientations of Proteins in Membranes (OPM), and PDBTM, as well as the extended dataset of mpstruc based on sequence similarity, the PDB structures whose classification field indicates that they are "membrane proteins" and the proteins with Structural Classification of Proteins (SCOP) class-f domains. We evaluated the relationships between these databases or datasets based on the overlap in their contents and the degree of consistency in the structural, topological, and functional classifications and in the transmembrane domain assignment.
MAJOR CONCLUSIONS
The membrane databases differ from each other in their coverage, and in the criteria that they use for annotation and classification. To ensure the efficient use of these databases, it is important to understand their differences and similarities. The establishment of more detailed and consistent annotations for the sequence, structure, membrane association, and function of membrane proteins is still required.
GENERAL SIGNIFICANCE
Considering the recent growth of experimentally determined structures, a broad survey and cumulative analysis of the sum of knowledge as presented in the membrane protein structure databases can be helpful to elucidate structures and functions of membrane proteins. We also aim to provide a framework for future research and classification of membrane proteins.
Topics: Algorithms; Animals; Databases, Protein; Humans; Membrane Proteins; Models, Molecular; Protein Structure, Tertiary; Proteome; Proteomics
PubMed: 29331638
DOI: 10.1016/j.bbamem.2018.01.005 -
Expert Review of Proteomics Aug 2017Integral membrane proteins and lipids constitute the bilayer membranes that surround cells and sub-cellular compartments, and modulate movements of molecules and... (Review)
Review
Integral membrane proteins and lipids constitute the bilayer membranes that surround cells and sub-cellular compartments, and modulate movements of molecules and information between them. Since membrane protein drug targets represent a disproportionately large segment of the proteome, technical developments need timely review. Areas covered: Publically available resources such as Pubmed were surveyed. Bottom-up proteomics analyses now allow efficient extraction and digestion such that membrane protein coverage is essentially complete, making up around one third of the proteome. However, this coverage relies upon hydrophilic loop regions while transmembrane domains are generally poorly covered in peptide-based strategies. Top-down mass spectrometry where the intact membrane protein is fragmented in the gas phase gives good coverage in transmembrane regions, and membrane fractions are yielding to high-throughput top-down proteomics. Exciting progress in native mass spectrometry of membrane protein complexes is providing insights into subunit stoichiometry and lipid binding, and cross-linking strategies are contributing critical in-vivo information. Expert commentary: It is clear from the literature that integral membrane proteins have yielded to advanced techniques in protein chemistry and mass spectrometry, with applications limited only by the imagination of investigators. Key advances toward translation to the clinic are emphasized.
Topics: Glycosylation; Humans; Mass Spectrometry; Membrane Proteins; Organelles; Proteomics
PubMed: 28737967
DOI: 10.1080/14789450.2017.1359545 -
Experimental and computational approaches for membrane protein insertion and topology determination.Methods (San Diego, Calif.) Jun 2024Membrane proteins play pivotal roles in a wide array of cellular processes and constitute approximately a quarter of the protein-coding genes across all organisms.... (Review)
Review
Membrane proteins play pivotal roles in a wide array of cellular processes and constitute approximately a quarter of the protein-coding genes across all organisms. Despite their ubiquity and biological significance, our understanding of these proteins remains notably less comprehensive compared to their soluble counterparts. This disparity in knowledge can be attributed, in part, to the inherent challenges associated with employing specialized techniques for the investigation of membrane protein insertion and topology. This review will center on a discussion of molecular biology methodologies and computational prediction tools designed to elucidate the insertion and topology of helical membrane proteins.
Topics: Membrane Proteins; Computational Biology; Humans; Models, Molecular
PubMed: 38604415
DOI: 10.1016/j.ymeth.2024.03.012 -
Methods in Molecular Biology (Clifton,... 2023β-barrel membrane proteins (βMPs), found in the outer membrane of gram-negative bacteria, mitochondria, and chloroplasts, play important roles in membrane anchoring,...
β-barrel membrane proteins (βMPs), found in the outer membrane of gram-negative bacteria, mitochondria, and chloroplasts, play important roles in membrane anchoring, pore formation, and enzyme activities. However, it is often difficult to determine their structures experimentally, and the knowledge of their structures is currently limited. We have developed a method to predict the 3D architectures of βMPs. We can accurately construct transmembrane domains of βMPs by predicting their strand registers, from which full 3D atomic structures are derived. Using 3D Beta-barrel Membrane Protein Predictor (3D-BMPP), we can further accurately model the extended beta barrels and loops in non-TM regions with overall greater structure prediction coverage. 3DBMPP is a general technique that can be applied to protein families with limited sequences as well as proteins with novel folds. Applications of 3DBMPP can be broadly applied to genome-wide βMPs structure prediction.
Topics: Membrane Proteins; Protein Domains; Bacterial Outer Membrane Proteins
PubMed: 36959455
DOI: 10.1007/978-1-0716-2974-1_17 -
International Journal of Molecular... May 2023Entangled motifs are found in one-third of protein domain structures, a reference set that contains mostly globular proteins. Their properties suggest a connection with...
Entangled motifs are found in one-third of protein domain structures, a reference set that contains mostly globular proteins. Their properties suggest a connection with co-translational folding. Here, we wish to investigate the presence and properties of entangled motifs in membrane protein structures. From existing databases, we build a non-redundant data set of membrane protein domains, annotated with the monotopic/transmembrane and peripheral/integral labels. We evaluate the presence of entangled motifs using the Gaussian entanglement indicator. We find that entangled motifs appear in one-fifth of transmembrane and one-fourth of monotopic proteins. Surprisingly, the main features of the distribution of the values of the entanglement indicator are similar to the reference case of general proteins. The distribution is conserved across different organisms. Differences with respect to the reference set emerge when considering the chirality of entangled motifs. Although the same chirality bias is found for single-winding motifs in both membrane and reference proteins, the bias is reversed, strikingly, for double-winding motifs only in the reference set. We speculate that these observations can be rationalized in terms of the constraints exerted on the nascent chain by the co-translational bio-genesis machinery, which is different for membrane and globular proteins.
Topics: Membrane Proteins; Protein Folding; Amino Acid Motifs
PubMed: 37298146
DOI: 10.3390/ijms24119193 -
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 -
Biochemical Society Transactions Dec 2018The inherent hydrophobicity of membrane proteins is a major barrier to membrane protein research and understanding. Their low stability and solubility in aqueous... (Review)
Review
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.
Topics: Membrane Proteins; Protein Engineering
PubMed: 30381335
DOI: 10.1042/BST20180140 -
Biochimica Et Biophysica Acta.... Sep 2022Non-ionic detergents are important tools for the investigation of interactions between membrane proteins and lipid membranes. Recent studies led to the question as to...
Non-ionic detergents are important tools for the investigation of interactions between membrane proteins and lipid membranes. Recent studies led to the question as to whether the ability to capture protein-lipid interactions depends on the properties of detergents or their concentration in purification buffers. To address this question, we present the synthesis of an asymmetric, hybrid detergent that combines the head groups of detergents with opposing delipidating properties. We discuss detergent properties and protein purification outcomes to reveal whether the properties of detergent micelles or the detergent concentration in purification buffers drive membrane protein delipidation. We anticipate that our findings will enable the development of rationally design detergents for future applications in membrane protein research.
Topics: Detergents; Lipids; Membrane Proteins; Micelles
PubMed: 35551920
DOI: 10.1016/j.bbamem.2022.183958