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Special Issue Editor

Dr. Dariusz Zakrzewicz

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Guest Editor

Institute of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Justus-Liebig-University Giessen, Giessen, Germany
Interests: pharmacology; drug discovery; translational medicine; proteomics; posttranslational modifications; protein arginine methylation; membrane-bound proteins; solute carriers (SLC); sodium taurocholate cotransporting polypeptide (NTCP); moonlighting proteins; enolase

Special Issue Information

Dear Colleagues,

Membrane proteins and cell-surface-associated biomolecules have a diverse range of well-established and classically characterized functions that help cells to communicate, maintain their shape, respond to various stimuli, and transport innumerable biomolecules in and out of the cell. In addition to these established activities, a number of membrane molecules possess alternative noncanonical features, which simultaneously perform multiple autonomous and often unrelated activities executed by distinct domains and motifs. Their discovery led to a resurrection of scientifically long-forgotten membrane molecules, thereby increasing their attractiveness as novel drug targets for human diseases. Here, particularly noteworthy is Na⁺-dependent taurocholate cotransporting peptide, a major hepatic bile acid transporter, which has recently been reported as a functional receptor for hepatitis B virus. Other examples include, but are not limited to, the G-protein-coupled receptor kinase-2 and membrane-associated plasminogen receptors such as enolase or glyceraldehyde-3-phosphate dehydrogenase.

Although a number of multitasking membrane proteins have recently been identified, thereby improving our understanding of cellular diversity and complexity, several noncanonical protein functions remain to be uncovered. Hence, identification and comprehensive analysis of these functional features will lead to important new insights into molecular mechanisms of human diseases and improved drug discovery strategies to produce novel therapeutics.

This Special Issue aims to collect original research and review articles focused on noncanonical functions of integral/peripheral membrane proteins and membrane-bound biomolecules and their indisputable importance in maintaining cellular homeostasis and in triggering pathological processes involved in the development and progression of various disorders.

Dr. Dariusz Zakrzewicz
Guest Editor

Manuscript Submission Information

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Keywords

Non-canonical protein function
Multitasking protein
Peripheral and integral membrane proteins
Membrane-associated biomolecule
Membrane transporter
Cell surface receptor
Signal transduction
Host-pathogen interaction
Protein-Protein interaction

Published Papers (2 papers)

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Research

Jump to: Review

39 pages, 14325 KiB

Open AccessArticle

Chip-Based Sensing of the Intercellular Transfer of Cell Surface Proteins: Regulation by the Metabolic State

by Günter A. Müller, Matthias H. Tschöp and Timo D. Müller

Biomedicines 2021, 9(10), 1452; https://doi.org/10.3390/biomedicines9101452 - 13 Oct 2021

Cited by 5 | Viewed by 2115

Abstract

Glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs) are anchored at the surface of mammalian blood and tissue cells through a carboxy-terminal GPI glycolipid. Eventually, they are released into incubation medium in vitro and blood in vivo and subsequently inserted into neighboring cells, potentially leading to inappropriate surface expression or lysis. To obtain first insight into the potential (patho)physiological relevance of intercellular GPI-AP transfer and its biochemical characterization, a cell-free chip- and microfluidic channel-based sensing system was introduced. For this, rat or human adipocyte or erythrocyte plasma membranes (PM) were covalently captured by the TiO₂ chip surface operating as the acceptor PM. To measure transfer between PM, donor erythrocyte or adipocyte PM were injected into the channels of a flow chamber, incubated, and washed out, and the type and amount of proteins which had been transferred to acceptor PM evaluated with specific antibodies. Antibody binding was detected as phase shift of horizontal surface acoustic waves propagating over the chip surface. Time- and temperature-dependent transfer, which did not rely on fusion of donor and acceptor PM, was detected for GPI-APs, but not typical transmembrane proteins. Transfer of GPI-APs was found to be prevented by α-toxin, which binds to the glycan core of GPI anchors, and serum proteins in concentration-dependent fashion. Blockade of transfer, which was restored by synthetic phosphoinositolglycans mimicking the glycan core of GPI anchors, led to accumulation in the chip channels of full-length GPI-APs in association with phospholipids and cholesterol in non-membrane structures. Strikingly, efficacy of transfer between adipocytes and erythrocytes was determined by the metabolic state (genotype and feeding state) of the rats, which were used as source for the PM and sera, with upregulation in obese and diabetic rats and counterbalance by serum proteins. The novel chip-based sensing system for GPI-AP transfer may be useful for the prediction and stratification of metabolic diseases as well as elucidation of the putative role of intercellular transfer of cell surface proteins, such as GPI-APs, in (patho)physiological mechanisms. Full article

(This article belongs to the Special Issue Non-canonical Functions of Membrane Proteins: Novel Opportunities for Drug Discovery)

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Review

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21 pages, 2342 KiB

Open AccessReview

Multitasking Na⁺/Taurocholate Cotransporting Polypeptide (NTCP) as a Drug Target for HBV Infection: From Protein Engineering to Drug Discovery

by Dariusz Zakrzewicz and Joachim Geyer

Biomedicines 2022, 10(1), 196; https://doi.org/10.3390/biomedicines10010196 - 17 Jan 2022

Cited by 11 | Viewed by 3462

Abstract

Hepatitis B virus (HBV) infections are among the major public health concerns worldwide with more than 250 million of chronically ill individuals. Many of them are additionally infected with the Hepatitis D virus, a satellite virus to HBV. Chronic infection frequently leads to serious liver diseases including cirrhosis and hepatocellular carcinoma, the most common type of liver cancer. Although current antiviral therapies can control HBV replication and slow down disease progress, there is an unmet medical need to identify therapies to cure this chronic infectious disease. Lately, a noteworthy progress in fighting against HBV has been made by identification of the high-affinity hepatic host receptor for HBV and HDV, namely Na⁺/taurocholate cotransporting polypeptide (NTCP, gene symbol SLC10A1). Next to its primary function as hepatic uptake transporter for bile acids, NTCP is essential for the cellular entry of HBV and HDV into hepatocytes. Due to this high-ranking discovery, NTCP has become a valuable target for drug development strategies for HBV/HDV-infected patients. In this review, we will focus on a newly predicted three-dimensional NTCP model that was generated using computational approaches and discuss its value in understanding the NTCP’s membrane topology, substrate and virus binding taking place in plasma membranes. We will review existing data on structural, functional, and biological consequences of amino acid residue changes and mutations that lead to loss of NTCP’s transport and virus receptor functions. Finally, we will discuss new directions for future investigations aiming at development of new NTCP-based HBV entry blockers that inhibit HBV tropism in human hepatocytes. Full article

(This article belongs to the Special Issue Non-canonical Functions of Membrane Proteins: Novel Opportunities for Drug Discovery)

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