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Advanced Research on Structure–Function Relationships of Membrane Proteins

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A special issue of Membranes (ISSN 2077-0375). This special issue belongs to the section "Biological Membrane Composition and Structures".

Deadline for manuscript submissions: closed (20 February 2022) | Viewed by 46866

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Prof. Dr. Akira Naito

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Guest Editor

Graduate School of Engineering, Yokohama National University, Yokohama 240-8501, Japan
Interests: structure–function relationships of ion pump membrane proteins; photoreaction pathways of retinal-binding membrane proteins; membrane-bound structure of antimicrobial peptides; amyloid fibril formation mechanism; development of solid-state NMR spectroscopy
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Dr. Izuru Kawamura

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Guest Editor

Graduate School of Engineering, Yokohama National University, Yokohama 240-8501, Japan
Interests: biological solid-state NMR; microbial rhodopsins; antimicrobial peptides; D-amino acid-containing peptides; cellulose nanofibers; membrane peptide interaction
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Membrane proteins embedded in biological membranes account for 30% of the proteins encoded in the human genome and play an essential role in maintaining the homeostasis of cells by functioning as transporters and in signal transaction and energy conversion, amongst other functions, and knowledge of the atomic resolution structure of membrane proteins is extremely important to understanding their functions. However, it is difficult to determine the structure of membrane proteins at the atomic resolution, as compared with soluble proteins, because of the difficulty of their crystallization.

Recent developments in the methodology of structure determination are providing high-resolution structures of membrane proteins, and a number of high-resolution structures of membrane proteins have been reported (~4% of PDB). Solid-state NMR spectroscopy does not require crystallization and is not restricted by the upper limits to molecular weight. Solution state NMR spectroscopy is recently used to determine structure of membrane proteins using nanodisc as a membrane mimic system. For X-ray crystallography, it is becoming possible to determine structures of membrane proteins by using membrane or membrane mimic systems to form the crystals. The recently developed time-resolved method allows determining the structure of short-lived intermediates of membrane proteins. Attention is now being focused on cryo-electron microscopy as a powerful method to determine the structure of membrane proteins using two-dimensional crystals. The determination of membrane protein structure based on single-molecule observation has also recently become possible.

This Special Issue will focus on advanced studies on structure–function relationships using advanced methods to determine the high-resolution structures of membrane proteins, including developments in methodology. Within the scope of this Special Issue are not only determinations of complete structure but also of local structure changes and the dynamic properties of membrane proteins.

Prof. Dr. Akira Naito
Prof. Dr. Izuru Kawamura
Guest Editors

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Keywords

membrane protein structure
membrane protein transporters
signal transduction
energy conversion
solid-state NMR
solution-state NMR
X-ray crystallography
cryo-electron microscopy

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Published Papers (12 papers)

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Editorial

Jump to: Research, Review

5 pages, 1791 KiB

Open AccessEditorial

Advanced Research on Structure–Function Relationships of Membrane Proteins

by Akira Naito and Izuru Kawamura

Membranes 2022, 12(7), 672; https://doi.org/10.3390/membranes12070672 - 29 Jun 2022

Viewed by 2102

Abstract

(This article belongs to the Special Issue Advanced Research on Structure–Function Relationships of Membrane Proteins)

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Research

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17 pages, 3736 KiB

Open AccessArticle

Photoreaction Pathways of Bacteriorhodopsin and Its D96N Mutant as Revealed by in Situ Photoirradiation Solid-State NMR

by Arisu Shigeta, Yuto Otani, Ryota Miyasa, Yoshiteru Makino, Izuru Kawamura, Takashi Okitsu, Akimori Wada and Akira Naito

Membranes 2022, 12(3), 279; https://doi.org/10.3390/membranes12030279 - 28 Feb 2022

Cited by 2 | Viewed by 3937

Abstract

Bacteriorhodopsin (BR) functions as a light-driven proton pump that transitions between different states during the photocycle, such as all-trans (AT; BR568) and 13-cis, 15-syn (CS; BR548) state and K, L, M₁, M₂, N, and O intermediates. In this study, we used in situ photoirradiation ¹³C solid-state NMR to observe a variety of photo-intermediates and photoreaction pathways in [20-¹³C]retinal-WT-BR and its mutant [20-¹³C, 14-¹³C]retinal-D96N-BR. In WT-BR, the CS state converted to the CS* intermediate under photoirradiation with green light at −20 °C and consequently converted to the AT state in the dark. The AT state converted to the N intermediate under irradiation with green light. In D96N-BR, the CS state was converted to the CS* intermediate at −30 °C and consequently converted to the AT state. Simultaneously, the AT state converted to the M and L intermediates under green light illumination at −30 °C and subsequently converted to the AT state in the dark. The M intermediate was directly excited to the AT state by UV light illumination. We demonstrated that short-lived photo-intermediates could be observed in a stationary state using in situ photoirradiation solid-state NMR spectroscopy for WT-BR and D96N-BR, enabling insight into the light-driven proton pump activity of BR. Full article

(This article belongs to the Special Issue Advanced Research on Structure–Function Relationships of Membrane Proteins)

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13 pages, 4117 KiB

Open AccessArticle

The Poly-Glutamate Motif of GmMATE4 Regulates Its Isoflavone Transport Activity

by Yee-Shan Ku, Sau-Shan Cheng, Ming-Yan Cheung, Yongchao Niu, Ailin Liu, Gyuhwa Chung and Hon-Ming Lam

Membranes 2022, 12(2), 206; https://doi.org/10.3390/membranes12020206 - 10 Feb 2022

Cited by 6 | Viewed by 2075

Abstract

Multidrug and toxic compound extrusion (MATE) transporters in eukaryotes have been characterized to be antiporters that mediate the transport of substrates in exchange for protons. In plants, alkaloids, phytohormones, ion chelators, and flavonoids have been reported to be the substrates of MATE transporters. Structural analyses have been conducted to dissect the functional significance of various motifs of MATE proteins. However, an understanding of the functions of the N- and C-termini has been inadequate. Here, by performing phylogenetic analyses and protein sequence alignment of 14 representative plant species, we identified a distinctive N-terminal poly-glutamate motif among a cluster of MATE proteins in soybean. Amongst them, GmMATE4 has the most consecutive glutamate residues at the N-terminus. A subcellular localization study showed that GmMATE4 was localized at the vacuolar membrane-like structure. Protein charge prediction showed that the mutation of the glutamate residues to alanine would reduce the negative charge at the N-terminus. Using yeast as the model, we showed that GmMATE4 mediated the transport of daidzein, genistein, glycitein, and glycitin. In addition, the glutamate-to-alanine mutation reduced the isoflavone transport capacity of GmMATE4. Altogether, we demonstrated GmMATE4 as an isoflavone transporter and the functional significance of the N-terminal poly-glutamate motif of GmMATE4 for regulating the isoflavone transport activity. Full article

(This article belongs to the Special Issue Advanced Research on Structure–Function Relationships of Membrane Proteins)

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15 pages, 1699 KiB

Open AccessArticle

Formation of β-Strand Oligomers of Antimicrobial Peptide Magainin 2 Contributes to Disruption of Phospholipid Membrane

by Munehiro Kumashiro, Ryoga Tsuji, Shoma Suenaga and Koichi Matsuo

Membranes 2022, 12(2), 131; https://doi.org/10.3390/membranes12020131 - 21 Jan 2022

Cited by 6 | Viewed by 3187

Abstract

The antimicrobial peptide magainin 2 (M2) interacts with and induces structural damage in bacterial cell membranes. Although extensive biophysical studies have revealed the interaction mechanism between M2 and membranes, the mechanism of membrane-mediated oligomerization of M2 is controversial. Here, we measured the synchrotron-radiation circular dichroism and linear dichroism (LD) spectra of M2 in dipalmitoyl-phosphatidylglycerol lipid membranes in lipid-to-peptide (L/P) molar ratios from 0–26 to characterize the conformation and orientation of M2 on the membrane. The results showed that M2 changed from random coil to α-helix structures via an intermediate state with increasing L/P ratio. Singular value decomposition analysis supported the presence of the intermediate state, and global fitting analysis revealed that M2 monomers with an α-helix structure assembled and transformed into M2 oligomers with a β-strand-rich structure in the intermediate state. In addition, LD spectra showed the presence of β-strand structures in the intermediate state, disclosing their orientations on the membrane surface. Furthermore, fluorescence spectroscopy showed that the formation of β-strand oligomers destabilized the membrane structure and induced the leakage of calcein molecules entrapped in the membrane. These results suggest that the formation of β-strand oligomers of M2 plays a crucial role in the disruption of the cell membrane. Full article

(This article belongs to the Special Issue Advanced Research on Structure–Function Relationships of Membrane Proteins)

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13 pages, 2616 KiB

Open AccessArticle

Cholesterol Modulates the Interaction between HIV-1 Viral Protein R and Membrane

by Chun-Hao Liu, Shing-Jong Huang and Tsyr-Yan Yu

Membranes 2021, 11(10), 784; https://doi.org/10.3390/membranes11100784 - 13 Oct 2021

Cited by 1 | Viewed by 2325

Abstract

Being a major metabolite for maintaining cellular homeostasis, as well as an important structural component in lipid membrane, cholesterol also plays critical roles in the life cycles of some viruses, including human immunodeficiency virus-1 (HIV-1). The involvement of cholesterol in HIV-1 infectivity, assembly and budding has made it an important research target. Viral protein R (Vpr) is an accessory protein of HIV-1, which is involved in many major events in the life cycle of HIV-1. In addition to its multi-functional roles in the HIV-1 life cycle, it is shown to interact with lipid membrane and form a cation-selective channel. In this work, we examined the effect of cholesterol on the interaction of Vpr and lipid membrane. Using calcein release assay, we found that the membrane permeability induced by the membrane binding of Vpr was significantly reduced in the presence of cholesterol in membrane. In addition, using solid-state NMR (ssNMR) spectroscopy, Vpr was shown to experience multiple chemical environments in lipid membrane, as indicated by the broad line shape of carbonyl ¹³C resonance of Cys-76 residue ranging from 165–178 ppm, which can be attributed to the existence of complex Vpr-membrane environments. We further showed that the presence of cholesterol in membrane will alter the distribution of Vpr in the complex membrane environments, which may explain the change of the Vpr induced membrane permeability in the presence of cholesterol. Full article

(This article belongs to the Special Issue Advanced Research on Structure–Function Relationships of Membrane Proteins)

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12 pages, 1763 KiB

Open AccessArticle

Structural Arrangement Produced by Concanavalin A Binding to Homomeric GluK2 Receptors

by Cuauhtemoc U. Gonzalez, Elisa Carrillo, Vladimir Berka and Vasanthi Jayaraman

Membranes 2021, 11(8), 613; https://doi.org/10.3390/membranes11080613 - 11 Aug 2021

Cited by 2 | Viewed by 4640

Abstract

Kainate receptors are members of the ionotropic glutamate receptor family. They form cation-specific transmembrane channels upon binding glutamate that desensitize in the continued presence of agonists. Concanavalin A (Con-A), a lectin, stabilizes the active open-channel state of the kainate receptor and reduces the extent of desensitization. In this study, we used single-molecule fluorescence resonance energy transfer (smFRET) to investigate the conformational changes underlying kainate receptor modulation by Con-A. These studies showed that Con-A binding to GluK2 homomeric kainate receptors resulted in closer proximity of the subunits at the dimer–dimer interface at the amino-terminal domain as well as between the subunits at the dimer interface at the agonist-binding domain. Additionally, the modulation of receptor functions by monovalent ions, which bind to the dimer interface at the agonist-binding domain, was not observed in the presence of Con-A. Based on these results, we conclude that Con-A modulation of kainate receptor function is mediated by a shift in the conformation of the kainate receptor toward a tightly packed extracellular domain. Full article

(This article belongs to the Special Issue Advanced Research on Structure–Function Relationships of Membrane Proteins)

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10 pages, 1041 KiB

Open AccessArticle

Small Residues Inhibit Homo-Dimerization of the Human Carbonic Anhydrase XII Transmembrane Domain

by Florian Cymer and Dirk Schneider

Membranes 2021, 11(7), 512; https://doi.org/10.3390/membranes11070512 - 7 Jul 2021

Cited by 1 | Viewed by 2493

Abstract

Amino acids with small side chains and motifs of small residues in a distance of four are rather abundant in human single-span transmembrane helices. While interaction of such helices appears to be common, the role of the small residues in mediating and/or stabilizing transmembrane helix oligomers remains mostly elusive. Yet, the mere existence of (small)xxx(small) motifs in transmembrane helices is frequently used to model dimeric TM helix structures. The single transmembrane helix of the human carbonic anhydrases XII contains a large number of amino acids with small side chains, and critical involvement of these small amino acids in dimerization of the transmembrane domain has been suggested. Using the GALLEX assay, we show here that the transmembrane domain indeed forms a strong transmembrane helix oligomer within a biological membrane. However, single or multiple mutations of small residue(s) to isoleucine almost always increased, rather than decreased, the interaction propensities. Reduction of helix flexibility and of protein–lipid contacts caused by a reduced lipid accessible surface area likely results in stabilization of helix–helix interactions within the membrane. Full article

(This article belongs to the Special Issue Advanced Research on Structure–Function Relationships of Membrane Proteins)

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Review

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16 pages, 1540 KiB

Open AccessEditor’s ChoiceReview

Biophysical Characterization of Membrane Proteins Embedded in Nanodiscs Using Fluorescence Correlation Spectroscopy

by Matthew J. Laurence, Timothy S. Carpenter, Ted A. Laurence, Matthew A. Coleman, Megan Shelby and Chao Liu

Membranes 2022, 12(4), 392; https://doi.org/10.3390/membranes12040392 - 31 Mar 2022

Cited by 1 | Viewed by 4849

Abstract

Proteins embedded in biological membranes perform essential functions in all organisms, serving as receptors, transporters, channels, cell adhesion molecules, and other supporting cellular roles. These membrane proteins comprise ~30% of all human proteins and are the targets of ~60% of FDA-approved drugs, yet their extensive characterization using established biochemical and biophysical methods has continued to be elusive due to challenges associated with the purification of these insoluble proteins. In response, the development of nanodisc techniques, such as nanolipoprotein particles (NLPs) and styrene maleic acid polymers (SMALPs), allowed membrane proteins to be expressed and isolated in solution as part of lipid bilayer rafts with defined, consistent nanometer sizes and compositions, thus enabling solution-based measurements. Fluorescence correlation spectroscopy (FCS) is a relatively simple yet powerful optical microscopy-based technique that yields quantitative biophysical information, such as diffusion kinetics and concentrations, about individual or interacting species in solution. Here, we first summarize current nanodisc techniques and FCS fundamentals. We then provide a focused review of studies that employed FCS in combination with nanodisc technology to investigate a handful of membrane proteins, including bacteriorhodopsin, bacterial division protein ZipA, bacterial membrane insertases SecYEG and YidC, Yersinia pestis type III secretion protein YopB, yeast cell wall stress sensor Wsc1, epidermal growth factor receptor (EGFR), ABC transporters, and several G protein-coupled receptors (GPCRs). Full article

(This article belongs to the Special Issue Advanced Research on Structure–Function Relationships of Membrane Proteins)

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19 pages, 2872 KiB

Open AccessReview

Endothelial Cell Plasma Membrane Biomechanics Mediates Effects of Pro-Inflammatory Factors on Endothelial Mechanosensors: Vicious Circle Formation in Atherogenic Inflammation

by Nadezhda Barvitenko, Mohammad Ashrafuzzaman, Alfons Lawen, Elisaveta Skverchinskaya, Carlota Saldanha, Alessia Manca, Giuseppe Uras, Muhammad Aslam and Antonella Pantaleo

Membranes 2022, 12(2), 205; https://doi.org/10.3390/membranes12020205 - 10 Feb 2022

Cited by 7 | Viewed by 2782

Abstract

Chronic low-grade vascular inflammation and endothelial dysfunction significantly contribute to the pathogenesis of cardiovascular diseases. In endothelial cells (ECs), anti-inflammatory or pro-inflammatory signaling can be induced by different patterns of the fluid shear stress (SS) exerted by blood flow on ECs. Laminar blood flow with high magnitude is anti-inflammatory, while disturbed flow and laminar flow with low magnitude is pro-inflammatory. Endothelial mechanosensors are the key upstream signaling proteins in SS-induced pro- and anti-inflammatory responses. Being transmembrane proteins, mechanosensors, not only experience fluid SS but also become regulated by the biomechanical properties of the lipid bilayer and the cytoskeleton. We review the apparent effects of pro-inflammatory factors (hypoxia, oxidative stress, hypercholesterolemia, and cytokines) on the biomechanics of the lipid bilayer and the cytoskeleton. An analysis of the available data suggests that the formation of a vicious circle may occur, in which pro-inflammatory cytokines enhance and attenuate SS-induced pro-inflammatory and anti-inflammatory signaling, respectively. Full article

(This article belongs to the Special Issue Advanced Research on Structure–Function Relationships of Membrane Proteins)

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17 pages, 5316 KiB

Open AccessReview

Heavy Atom Detergent/Lipid Combined X-ray Crystallography for Elucidating the Structure-Function Relationships of Membrane Proteins

by Shinya Hanashima, Takanori Nakane and Eiichi Mizohata

Membranes 2021, 11(11), 823; https://doi.org/10.3390/membranes11110823 - 27 Oct 2021

Cited by 6 | Viewed by 2672

Abstract

Membrane proteins reside in the lipid bilayer of biomembranes and the structure and function of these proteins are closely related to their interactions with lipid molecules. Structural analyses of interactions between membrane proteins and lipids or detergents that constitute biological or artificial model membranes are important for understanding the functions and physicochemical properties of membrane proteins and biomembranes. Determination of membrane protein structures is much more difficult when compared with that of soluble proteins, but the development of various new technologies has accelerated the elucidation of the structure-function relationship of membrane proteins. This review summarizes the development of heavy atom derivative detergents and lipids that can be used for structural analysis of membrane proteins and their interactions with detergents/lipids, including their application with X-ray free-electron laser crystallography. Full article

(This article belongs to the Special Issue Advanced Research on Structure–Function Relationships of Membrane Proteins)

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29 pages, 2414 KiB

Open AccessEditor’s ChoiceReview

Lipid Membrane Mimetics in Functional and Structural Studies of Integral Membrane Proteins

by Saman Majeed, Akram Bani Ahmad, Ujala Sehar and Elka R. Georgieva

Membranes 2021, 11(9), 685; https://doi.org/10.3390/membranes11090685 - 3 Sep 2021

Cited by 36 | Viewed by 9482

Abstract

Integral membrane proteins (IMPs) fulfill important physiological functions by providing cell–environment, cell–cell and virus–host communication; nutrients intake; export of toxic compounds out of cells; and more. However, some IMPs have obliterated functions due to polypeptide mutations, modifications in membrane properties and/or other environmental factors—resulting in damaged binding to ligands and the adoption of non-physiological conformations that prevent the protein from returning to its physiological state. Thus, elucidating IMPs’ mechanisms of function and malfunction at the molecular level is important for enhancing our understanding of cell and organism physiology. This understanding also helps pharmaceutical developments for restoring or inhibiting protein activity. To this end, in vitro studies provide invaluable information about IMPs’ structure and the relation between structural dynamics and function. Typically, these studies are conducted on transferred from native membranes to membrane-mimicking nano-platforms (membrane mimetics) purified IMPs. Here, we review the most widely used membrane mimetics in structural and functional studies of IMPs. These membrane mimetics are detergents, liposomes, bicelles, nanodiscs/Lipodisqs, amphipols, and lipidic cubic phases. We also discuss the protocols for IMPs reconstitution in membrane mimetics as well as the applicability of these membrane mimetic-IMP complexes in studies via a variety of biochemical, biophysical, and structural biology techniques. Full article

(This article belongs to the Special Issue Advanced Research on Structure–Function Relationships of Membrane Proteins)

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16 pages, 1530 KiB

Open AccessReview

by Koh Takeuchi, Yutaka Kofuku, Shunsuke Imai, Takumi Ueda, Yuji Tokunaga, Yuki Toyama, Yutaro Shiraishi and Ichio Shimada

Membranes 2021, 11(8), 604; https://doi.org/10.3390/membranes11080604 - 9 Aug 2021

Cited by 2 | Viewed by 3121

Abstract

A primary biological function of multi-spanning membrane proteins is to transfer information and/or materials through a membrane by changing their conformations. Therefore, particular dynamics of the membrane proteins are tightly associated with their function. The semi-atomic resolution dynamics information revealed by NMR is able to discriminate function-related dynamics from random fluctuations. This review will discuss several studies in which quantitative dynamics information by solution NMR has contributed to revealing the structural basis of the function of multi-spanning membrane proteins, such as ion channels, GPCRs, and transporters. Full article

(This article belongs to the Special Issue Advanced Research on Structure–Function Relationships of Membrane Proteins)

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