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Membrane Proteins in Human Health and Disease
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Membrane Proteins in Human Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 11145

Special Issue Editor

Prof. Dr. Wade D. Van Horn

E-Mail Website
Guest Editor
The Virginia G. Piper Biodesign Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA
Interests: TRP channels; ion channels; membrane protein; biophysics; NMR; protein dynamics

Special Issue Information

Dear Colleagues,

Membrane proteins function in virtually all aspects of biology. On account of their diverse roles, membrane protein mutations can cause misfolding, maltrafficking, and dysfunction, leading to significant human pathophysiologies. Additionally, because membrane proteins are at the heart of signal transduction and material transport, this class of proteins comprises the most common targets for therapeutic intervention. Molecular studies of membrane proteins provide a mechanistic framework to better understand the root causes of disease and to produce insight into the development and efficacy of therapeutic intervention.

This Special Issue, titled “Membrane Proteins in Human Health and Disease”, of the International Journal of Molecular Sciences will comprise a selection of research papers and reviews that probe functional, structural, and dynamical aspects of the roles that membrane proteins play in human health and disease. In particular, molecular-based studies of ion channels, G-protein coupled receptors, transporters, and other family member studies that provide mechanistic insight into function or dysfunction are the primary foci for this Issue. This includes computational-, structural-, biochemical-, and biophysical-based investigations, broadly speaking. Pure clinical or investigational studies are not suitable for this Issue; however, clinical submissions with biomolecular experiments are welcomed.

Prof. Dr. Wade D. Van Horn
Guest Editor

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 special issue 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • Membrane proteins
  • GPCRs
  • Transporters
  • Ion channels
  • Receptors
  • Computation
  • Spectroscopy
  • Membrane biophysics
  • Membrane protein structure
  • Membrane protein function
  • Membrane protein trafficking
  • Membrane protein folding

Published Papers (4 papers)

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Research

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20 pages, 4288 KiB  
Article
Rare Gain-of-Function KCND3 Variant Associated with Cerebellar Ataxia, Parkinsonism, Cognitive Dysfunction, and Brain Iron Accumulation
by Cheng-Tsung Hsiao, Thomas F. Tropea, Ssu-Ju Fu, Tanya M. Bardakjian, Pedro Gonzalez-Alegre, Bing-Wen Soong, Chih-Yung Tang and Chung-Jiuan Jeng
Int. J. Mol. Sci. 2021, 22(15), 8247; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158247 - 31 Jul 2021
Cited by 6 | Viewed by 2192
Abstract
Loss-of-function mutations in the KV4.3 channel-encoding KCND3 gene are linked to neurodegenerative cerebellar ataxia. Patients suffering from neurodegeneration associated with iron deposition may also present with cerebellar ataxia. The mechanism underlying brain iron accumulation remains unclear. Here, we aim to ascertain [...] Read more.
Loss-of-function mutations in the KV4.3 channel-encoding KCND3 gene are linked to neurodegenerative cerebellar ataxia. Patients suffering from neurodegeneration associated with iron deposition may also present with cerebellar ataxia. The mechanism underlying brain iron accumulation remains unclear. Here, we aim to ascertain the potential pathogenic role of KCND3 variant in iron accumulation-related cerebellar ataxia. We presented a patient with slowly progressive cerebellar ataxia, parkinsonism, cognitive impairment, and iron accumulation in the basal ganglia and the cerebellum. Whole exome sequencing analyses identified in the patient a heterozygous KCND3 c.1256G>A (p.R419H) variant predicted to be disease-causing by multiple bioinformatic analyses. In vitro biochemical and immunofluorescence examinations revealed that, compared to the human KV4.3 wild-type channel, the p.R419H variant exhibited normal protein abundance and subcellular localization pattern. Electrophysiological investigation, however, demonstrated that the KV4.3 p.R419H variant was associated with a dominant increase in potassium current amplitudes, as well as notable changes in voltage-dependent gating properties leading to enhanced potassium window current. These observations indicate that, in direct contrast with the loss-of-function KCND3 mutations previously reported in cerebellar ataxia patients, we identified a rare gain-of-function KCND3 variant that may expand the clinical and molecular spectra of neurodegenerative cerebellar disorders associated with brain iron accumulation. Full article
(This article belongs to the Special Issue Membrane Proteins in Human Health and Disease)
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14 pages, 3763 KiB  
Article
Unique Regulation of Intestinal Villus Epithelial Cl−/HCO3− Exchange by Cyclooxygenase Pathway Metabolites of Arachidonic Acid in a Mouse Model of Spontaneous Ileitis
by M Motiur Rahman, Alip Borthakur, Sheuli Afroz, Subha Arthur and Uma Sundaram
Int. J. Mol. Sci. 2021, 22(8), 4171; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084171 - 17 Apr 2021
Cited by 1 | Viewed by 1980
Abstract
Electrolytes (NaCl) and fluid malabsorption cause diarrhea in inflammatory bowel disease (IBD). Coupled NaCl absorption, mediated by Na+/H+ and Cl−/HCO3− exchanges on the intestinal villus cells brush border membrane (BBM), is inhibited in IBD. Arachidonic acid [...] Read more.
Electrolytes (NaCl) and fluid malabsorption cause diarrhea in inflammatory bowel disease (IBD). Coupled NaCl absorption, mediated by Na+/H+ and Cl−/HCO3− exchanges on the intestinal villus cells brush border membrane (BBM), is inhibited in IBD. Arachidonic acid metabolites (AAMs) formed via cyclooxygenase (COX) or lipoxygenase (LOX) pathways are elevated in IBD. However, their effects on NaCl absorption are not known. We treated SAMP1/YitFc (SAMP1) mice, a model of spontaneous ileitis resembling human IBD, with Arachidonyl Trifluoro Methylketone (ATMK, AAM inhibitor), or with piroxicam or MK-886, to inhibit COX or LOX pathways, respectively. Cl−/HCO3− exchange, measured as DIDS-sensitive 36Cl uptake, was significantly inhibited in villus cells and BBM vesicles of SAMP1 mice compared to AKR/J controls, an effect reversed by ATMK. Piroxicam, but not MK-886, also reversed the inhibition. Kinetic studies showed that inhibition was secondary to altered Km with no effects on Vmax. Whole cell or BBM protein levels of Down-Regulated in Adenoma (SLC26A3) and putative anion transporter-1 (SLC26A6), the two key BBM Cl−/HCO3− exchangers, were unaltered. Thus, inhibition of villus cell Cl−/HCO3− exchange by COX pathway AAMs, such as prostaglandins, via reducing the affinity of the exchanger for Cl−, and thereby causing NaCl malabsorption, could significantly contribute to IBD-associated diarrhea. Full article
(This article belongs to the Special Issue Membrane Proteins in Human Health and Disease)
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18 pages, 6225 KiB  
Article
ABCG2 Is Overexpressed on Red Blood Cells in Ph-Negative Myeloproliferative Neoplasms and Potentiates Ruxolitinib-Induced Apoptosis
by Ralfs Buks, Mégane Brusson, Sylvie Cochet, Tatiana Galochkina, Bruno Cassinat, Ivan Nemazanyy, Thierry Peyrard, Jean-Jacques Kiladjian, Alexandre G. de Brevern, Slim Azouzi and Wassim El Nemer
Int. J. Mol. Sci. 2021, 22(7), 3530; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073530 - 29 Mar 2021
Cited by 3 | Viewed by 2933
Abstract
Myeloproliferative neoplasms (MPNs) are a group of disorders characterized by clonal expansion of abnormal hematopoietic stem cells leading to hyperproliferation of one or more myeloid lineages. The main complications in MPNs are high risk of thrombosis and progression to myelofibrosis and leukemia. MPN [...] Read more.
Myeloproliferative neoplasms (MPNs) are a group of disorders characterized by clonal expansion of abnormal hematopoietic stem cells leading to hyperproliferation of one or more myeloid lineages. The main complications in MPNs are high risk of thrombosis and progression to myelofibrosis and leukemia. MPN patients with high risk scores are treated by hydroxyurea (HU), interferon-α, or ruxolitinib, a tyrosine kinase inhibitor. Polycythemia vera (PV) is an MPN characterized by overproduction of red blood cells (RBCs). ABCG2 is a member of the ATP-binding cassette superfamily transporters known to play a crucial role in multidrug resistance development. Proteome analysis showed higher ABCG2 levels in PV RBCs compared to RBCs from healthy controls and an additional increase of these levels in PV patients treated with HU, suggesting that ABCG2 might play a role in multidrug resistance in MPNs. In this work, we explored the role of ABCG2 in the transport of ruxolitinib and HU using human cell lines, RBCs, and in vitro differentiated erythroid progenitors. Using stopped-flow analysis, we showed that HU is not a substrate for ABCG2. Using transfected K562 cells expressing three different levels of recombinant ABCG2, MPN RBCs, and cultured erythroblasts, we showed that ABCG2 potentiates ruxolitinib-induced cytotoxicity that was blocked by the ABCG2-specific inhibitor KO143 suggesting ruxolitinib intracellular import by ABCG2. In silico modeling analysis identified possible ruxolitinib-binding site locations within the cavities of ABCG2. Our study opens new perspectives in ruxolitinib efficacy research targeting cell types depending on ABCG2 expression and polymorphisms among patients. Full article
(This article belongs to the Special Issue Membrane Proteins in Human Health and Disease)
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Review

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17 pages, 4557 KiB  
Review
The Multifunctional Role of EMP3 in the Regulation of Membrane Receptors Associated with IDH-Wild-Type Glioblastoma
by Antoni Andreu Martija and Stefan Pusch
Int. J. Mol. Sci. 2021, 22(10), 5261; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105261 - 17 May 2021
Cited by 5 | Viewed by 3035
Abstract
Epithelial membrane protein 3 (EMP3) is a tetraspan membrane protein overexpressed in isocitrate dehydrogenase-wild-type (IDH-wt) glioblastoma (GBM). Several studies reported high EMP3 levels as a poor prognostic factor in GBM patients. Experimental findings based on glioma and non-glioma models have demonstrated the role [...] Read more.
Epithelial membrane protein 3 (EMP3) is a tetraspan membrane protein overexpressed in isocitrate dehydrogenase-wild-type (IDH-wt) glioblastoma (GBM). Several studies reported high EMP3 levels as a poor prognostic factor in GBM patients. Experimental findings based on glioma and non-glioma models have demonstrated the role of EMP3 in the regulation of several membrane proteins known to drive IDH-wt GBM. In this review, we summarize what is currently known about EMP3 biology. We discuss the regulatory effects that EMP3 exerts on a variety of oncogenic receptors and discuss how these mechanisms may relate to IDH-wt GBM. Lastly, we enumerate the open questions towards EMP3 function in IDH-wt GBM. Full article
(This article belongs to the Special Issue Membrane Proteins in Human Health and Disease)
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