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Membranes
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Membrane Protein Structure and Functions
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Membrane Protein Structure and Functions (Closed)

A topical collection in Membranes (ISSN 2077-0375). This collection belongs to the section "Biological Membranes".

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Editors

Dr. Marco Lolicato

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Guest Editor
Dipartimento di Medicina Molecolare, Università di Pavia, Pavia, Italy
Interests: protein structure; biophysics of ion channels; channel activation
Dr. Cristina Arrigoni

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Guest Editor
Dipartimento di Medicina Molecolare, Università di Pavia, Pavia, Italy
Interests: ion channel biophysics; electrophysiology; GPCRs

Topical Collection Information

Dear Colleagues,

Membrane proteins encompass about 30% of the whole proteome and represent more than 40% of the total drug targets. The combination of structural biology and functional characterization approaches has been extremely successful in understanding the molecular mechanisms behind their physiological function, opening new venues for drug development. In this Special Issue, we aim to present both original papers and reviews to offer an overview of the structure and function of membrane proteins, with a focus on the tremendous impacts of newly available biochemical reagents and the recent technological advances in structural determination. This collection will provide state-of-the-art knowledge on a class of proteins that is notoriously difficult to handle and it will highlight the anticipated new challenges that scientists will have to overcome to enrich our mechanistic understanding of the physiology taking place in the membrane. 

Dr. Marco Lolicato
Dr. Cristina Arrigoni
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the collection website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Membranes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Crystallography
  • Cryo-EM
  • Electrophysiology
  • Liposomes
  • Nanodiscs
  • Micelles
  • Detergents
  • Ion channels
  • GPCR
  • Transporters
  • Membrane enzymes
  • Lipids
  • Bicelles
  • SMALP

Published Papers (6 papers)

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2023

Jump to: 2022, 2021

9 pages, 1272 KiB  
Communication
The Human PDZome 2.0: Characterization of a New Resource to Test for PDZ Interactions by Yeast Two-Hybrid
by Monica Castro-Cruz, Frédérique Lembo, Jean-Paul Borg, Gilles Travé, Renaud Vincentelli and Pascale Zimmermann
Membranes 2023, 13(8), 737; https://doi.org/10.3390/membranes13080737 - 17 Aug 2023
Cited by 1 | Viewed by 2023
Abstract
PSD95-disc large-zonula occludens (PDZ) domains are globular modules of 80–90 amino acids that co-evolved with multicellularity. They commonly bind to carboxy-terminal sequences of a plethora of membrane-associated proteins and influence their trafficking and signaling. We previously built a PDZ resource (PDZome) allowing us [...] Read more.
PSD95-disc large-zonula occludens (PDZ) domains are globular modules of 80–90 amino acids that co-evolved with multicellularity. They commonly bind to carboxy-terminal sequences of a plethora of membrane-associated proteins and influence their trafficking and signaling. We previously built a PDZ resource (PDZome) allowing us to unveil human PDZ interactions by Yeast two-hybrid. Yet, this resource is incomplete according to the current knowledge on the human PDZ proteome. Here we built the PDZome 2.0 library for Yeast two-hybrid, based on a PDZ library manually curated from online resources. The PDZome2.0 contains 305 individual clones (266 PDZ domains in isolation and 39 tandems), for which all boundaries were designed based on available PDZ structures. Using as bait the E6 oncoprotein from HPV16, a known promiscuous PDZ interactor, we show that PDZome 2.0 outperforms the previous resource. Full article
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2022

Jump to: 2023, 2021

12 pages, 2723 KiB  
Article
Protons in Gating the Kv1.2 Channel: A Calculated Set of Protonation States in Response to Polarization/Depolarization of the Channel, with the Complete Proposed Proton Path from Voltage Sensing Domain to Gate
by Alisher M. Kariev and Michael E. Green
Membranes 2022, 12(7), 718; https://doi.org/10.3390/membranes12070718 - 20 Jul 2022
Cited by 2 | Viewed by 2461
Abstract
We have in the past proposed that proton motion constitutes the gating current in the potassium channel Kv1.2 and is responsible for the gating mechanism. For this to happen, there must be a proton path between the voltage-sensing domain (VSD) and [...] Read more.
We have in the past proposed that proton motion constitutes the gating current in the potassium channel Kv1.2 and is responsible for the gating mechanism. For this to happen, there must be a proton path between the voltage-sensing domain (VSD) and the channel gate, and here we present quantum calculations that lead to a specific pair of proton paths, defined at the molecular level, with well-defined water molecule linkages, and with hydrogen bonding between residues; there is also at least one interpath crossover, where protons can switch paths. Quantum calculations on the entire 563-atom system give the complete geometry, the energy, and atomic charges. Calculations show that three specific residues (in the pdb 3Lut numbering, H418, E327, R326), and the T1 intracellular moiety, all of which have been shown experimentally to be involved in gating, would necessarily be protonated or deprotonated in the path between the VSD and the gate. Hydroxyl reorientation of serine and threonine residues are shown to provide a means of adjusting proton directions of motion. In the deprotonated state for K312, a low energy state, our calculations come close to reproducing the X-ray structure. The demonstration of the existence of a double proton path between VSD and gate supports the proposed proton gating mechanism; when combined with our earlier demonstration of proton generation in the VSD, and comparison with other systems that are known to move protons, we are close to achieving the definition of a complete gating mechanism in molecular detail. The coupling of the paths to the VSD, and to the PVPV section that essentially forms the gate, can be easily seen from the results of the calculation. The gate itself remains for further computations. Full article
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15 pages, 2478 KiB  
Article
Angiostrongylus cantonensis an Atypical Presenilin: Epitope Mapping, Characterization, and Development of an ELISA Peptide Assay for Specific Diagnostic of Angiostrongyliasis
by Salvatore G. De-Simone, Paloma Napoleão-Pêgo, Priscila S. Gonçalves, Guilherme C. Lechuga, Arnaldo Mandonado, Jr., Carlos Graeff-Teixeira and David W. Provance, Jr.
Membranes 2022, 12(2), 108; https://doi.org/10.3390/membranes12020108 - 19 Jan 2022
Cited by 2 | Viewed by 2248
Abstract
Background: Angiostrongyliasis, the leading cause universal of eosinophilic meningitis, is an emergent disease due to Angiostrongylus cantonensis (rat lungworm) larvae, transmitted accidentally to humans. The diagnosis of human angiostrongyliasis is based on epidemiologic characteristics, clinical symptoms, medical history, and laboratory findings, particularly hypereosinophilia [...] Read more.
Background: Angiostrongyliasis, the leading cause universal of eosinophilic meningitis, is an emergent disease due to Angiostrongylus cantonensis (rat lungworm) larvae, transmitted accidentally to humans. The diagnosis of human angiostrongyliasis is based on epidemiologic characteristics, clinical symptoms, medical history, and laboratory findings, particularly hypereosinophilia in blood and cerebrospinal fluid. Thus, the diagnosis is difficult and often confused with those produced by other parasitic diseases. Therefore, the development of a fast and specific diagnostic test for angiostrongyliasis is a challenge mainly due to the lack of specificity of the described tests, and therefore, the characterization of a new target is required. Material and Methods: Using bioinformatics tools, the putative presenilin (PS) protein C7BVX5-1 was characterized structurally and phylogenetically. A peptide microarray approach was employed to identify single and specific epitopes, and tetrameric epitope peptides were synthesized to evaluate their performance in an ELISA-peptide assay. Results: The data showed that the A. cantonensis PS protein presents nine transmembrane domains, the catalytic aspartyl domain [(XD (aa 241) and GLGD (aa 332–335)], between TM6 and TM7 and the absence of the PALP and other characteristics domains of the class A22 and homologous presenilin (PSH). These individualities make it an atypical sub-branch of the PS family, located in a separate subgroup along with the enzyme Haemogonchus contournus and separated from other worm subclasses. Twelve B-linear epitopes were identified by microarray of peptides and validated by ELISA using infected rat sera. In addition, their diagnostic performance was demonstrated by an ELISA-MAP4 peptide. Conclusions: Our data show that the putative AgPS is an atypical multi-pass transmembrane protein and indicate that the protein is an excellent immunological target with two (PsAg3 and PsAg9) A. costarisencis cross-reactive epitopes and eight (PsAg1, PsAg2, PsAg6, PsAg7, PsAg8, PsAg10, PsAg11, PsAg12) apparent unique A. cantonensis epitopes. These epitopes could be used in engineered receptacle proteins to develop a specific immunological diagnostic assay for angiostrongyliasis caused by A. cantonensis. Full article
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2021

Jump to: 2023, 2022

11 pages, 1919 KiB  
Article
Enhancing the Cell-Free Expression of Native Membrane Proteins by In Silico Optimization of the Coding Sequence—An Experimental Study of the Human Voltage-Dependent Anion Channel
by Sonja Zayni, Samar Damiati, Susana Moreno-Flores, Fabian Amman, Ivo Hofacker, David Jin and Eva-Kathrin Ehmoser
Membranes 2021, 11(10), 741; https://doi.org/10.3390/membranes11100741 - 28 Sep 2021
Cited by 2 | Viewed by 3379
Abstract
Membrane proteins are involved in many aspects of cellular biology; for example, they regulate how cells interact with their environment, so such proteins are important drug targets. The rapid advancement in the field of immune effector cell therapy has been expanding the horizons [...] Read more.
Membrane proteins are involved in many aspects of cellular biology; for example, they regulate how cells interact with their environment, so such proteins are important drug targets. The rapid advancement in the field of immune effector cell therapy has been expanding the horizons of synthetic membrane receptors in the areas of cell-based immunotherapy and cellular medicine. However, the investigation of membrane proteins, which are key constituents of cells, is hampered by the difficulty and complexity of their in vitro synthesis, which is of unpredictable yield. Cell-free synthesis is herein employed to unravel the impact of the expression construct on gene transcription and translation, without the complex regulatory mechanisms of cellular systems. Through the systematic design of plasmids in the immediacy of the start of the target gene, it was possible to identify translation initiation and the conformation of mRNA as the main factors governing the cell-free expression efficiency of the human voltage-dependent anion channel (VDAC), which is a relevant membrane protein in drug-based therapy. A simple translation initiation model was developed to quantitatively assess the expression potential for the designed constructs. A scoring function that quantifies the feasibility of the formation of the translation initiation complex through the ribosome–mRNA hybridization energy and the accessibility of the mRNA segment binding to the ribosome is proposed. The scoring function enables one to optimize plasmid sequences and semi-quantitatively predict protein expression efficiencies. This scoring function is publicly available as webservice XenoExpressO at University of Vienna, Austria. Full article
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13 pages, 1492 KiB  
Review
Rush Hour of LATs towards Their Transport Cycle
by Adrià Nicolàs-Aragó, Joana Fort, Manuel Palacín and Ekaitz Errasti-Murugarren
Membranes 2021, 11(8), 602; https://doi.org/10.3390/membranes11080602 - 8 Aug 2021
Cited by 8 | Viewed by 3049
Abstract
The mammalian SLC7 family comprises the L-amino acid transporters (LATs) and the cationic amino acid transporters (CATs). The relevance of these transporters is highlighted by their involvement in several human pathologies, including inherited rare diseases and acquired diseases, such as cancer. In the [...] Read more.
The mammalian SLC7 family comprises the L-amino acid transporters (LATs) and the cationic amino acid transporters (CATs). The relevance of these transporters is highlighted by their involvement in several human pathologies, including inherited rare diseases and acquired diseases, such as cancer. In the last four years, several crystal or cryo-EM structures of LATs and CATs have been solved. These structures have started to fill our knowledge gap that previously was based on the structural biology of remote homologs of the amino acid–polyamine–organocation (APC) transporters. This review recovers this structural and functional information to start generating the molecular bases of the transport cycle of LATs. Special attention is given to the known transporter conformations within the transport cycle and the molecular bases for substrate interaction and translocation, including the asymmetric interaction of substrates at both sides of the plasma membrane. Full article
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21 pages, 6894 KiB  
Article
COMTOP: Protein Residue–Residue Contact Prediction through Mixed Integer Linear Optimization
by Md. Selim Reza, Huiling Zhang, Md. Tofazzal Hossain, Langxi Jin, Shengzhong Feng and Yanjie Wei
Membranes 2021, 11(7), 503; https://doi.org/10.3390/membranes11070503 - 30 Jun 2021
Cited by 3 | Viewed by 4810
Abstract
Protein contact prediction helps reconstruct the tertiary structure that greatly determines a protein’s function; therefore, contact prediction from the sequence is an important problem. Recently there has been exciting progress on this problem, but many of the existing methods are still low quality [...] Read more.
Protein contact prediction helps reconstruct the tertiary structure that greatly determines a protein’s function; therefore, contact prediction from the sequence is an important problem. Recently there has been exciting progress on this problem, but many of the existing methods are still low quality of prediction accuracy. In this paper, we present a new mixed integer linear programming (MILP)-based consensus method: a Consensus scheme based On a Mixed integer linear opTimization method for prOtein contact Prediction (COMTOP). The MILP-based consensus method combines the strengths of seven selected protein contact prediction methods, including CCMpred, EVfold, DeepCov, NNcon, PconsC4, plmDCA, and PSICOV, by optimizing the number of correctly predicted contacts and achieving a better prediction accuracy. The proposed hybrid protein residue–residue contact prediction scheme was tested in four independent test sets. For 239 highly non-redundant proteins, the method showed a prediction accuracy of 59.68%, 70.79%, 78.86%, 89.04%, 94.51%, and 97.35% for top-5L, top-3L, top-2L, top-L, top-L/2, and top-L/5 contacts, respectively. When tested on the CASP13 and CASP14 test sets, the proposed method obtained accuracies of 75.91% and 77.49% for top-L/5 predictions, respectively. COMTOP was further tested on 57 non-redundant α-helical transmembrane proteins and achieved prediction accuracies of 64.34% and 73.91% for top-L/2 and top-L/5 predictions, respectively. For all test datasets, the improvement of COMTOP in accuracy over the seven individual methods increased with the increasing number of predicted contacts. For example, COMTOP performed much better for large number of contact predictions (such as top-5L and top-3L) than for small number of contact predictions such as top-L/2 and top-L/5. The results and analysis demonstrate that COMTOP can significantly improve the performance of the individual methods; therefore, COMTOP is more robust against different types of test sets. COMTOP also showed better/comparable predictions when compared with the state-of-the-art predictors. Full article
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