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Importance of tyrosine phosphorylation for transmembrane signaling in plants.
Mühlenbeck, H, Bender, KW, Zipfel, C
The Biochemical journal. 2021;(14):2759-2774
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Abstract
Reversible protein phosphorylation is a widespread post-translational modification fundamental for signaling across all domains of life. Tyrosine (Tyr) phosphorylation has recently emerged as being important for plant receptor kinase (RK)-mediated signaling, particularly during plant immunity. How Tyr phosphorylation regulates RK function is however largely unknown. Notably, the expansion of protein Tyr phosphatase and SH2 domain-containing protein families, which are the core of regulatory phospho-Tyr (pTyr) networks in choanozoans, did not occur in plants. Here, we summarize the current understanding of plant RK Tyr phosphorylation focusing on the critical role of a pTyr site ('VIa-Tyr') conserved in several plant RKs. Furthermore, we discuss the possibility of metazoan-like pTyr signaling modules in plants based on atypical components with convergent biochemical functions.
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Regulated Intramembrane Proteolysis of ACE2: A Potential Mechanism Contributing to COVID-19 Pathogenesis?
Gonzalez, SM, Siddik, AB, Su, RC
Frontiers in immunology. 2021;:612807
Abstract
Since being identified as a key receptor for SARS-CoV-2, Angiotensin converting enzyme 2 (ACE2) has been studied as one of the potential targets for the development of preventative and/or treatment options. Tissue expression of ACE2 and the amino acids interacting with the spike protein of SARS-CoV-2 have been mapped. Furthermore, the recombinant soluble extracellular domain of ACE2 is already in phase 2 trials as a treatment for SARS-CoV-2 infection. Most studies have continued to focus on the ACE2 extracellular domain, which is known to play key roles in the renin angiotensin system and in amino acid uptake. However, few also found ACE2 to have an immune-modulatory function and its intracellular tail may be one of the signaling molecules in regulating cellular activation. The implication of its immune-modulatory role in preventing the cytokine-storm, observed in severe COVID-19 disease outcomes requires further investigation. This review focuses on the regulated proteolytic cleavage of ACE2 upon binding to inducer(s), such as the spike protein of SARS-CoV, the potential of cleaved ACE2 intracellular subdomain in regulating cellular function, and the ACE2's immune-modulatory function. This knowledge is critical for targeting ACE2 levels for developing prophylactic treatment or preventative measures in SARS-CoV infections.
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The roles of lipids in SARS-CoV-2 viral replication and the host immune response.
Theken, KN, Tang, SY, Sengupta, S, FitzGerald, GA
Journal of lipid research. 2021;:100129
Abstract
The significant morbidity and mortality associated with severe acute respiratory syndrome coronavirus 2 infection has underscored the need for novel antiviral strategies. Lipids play essential roles in the viral life cycle. The lipid composition of cell membranes can influence viral entry by mediating fusion or affecting receptor conformation. Upon infection, viruses can reprogram cellular metabolism to remodel lipid membranes and fuel the production of new virions. Furthermore, several classes of lipid mediators, including eicosanoids and sphingolipids, can regulate the host immune response to viral infection. Here, we summarize the existing literature on the mechanisms through which these lipid mediators may regulate viral burden in COVID-19. Furthermore, we define the gaps in knowledge and identify the core areas in which lipids offer therapeutic promise for severe acute respiratory syndrome coronavirus 2.
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Membrane Activity and Channel Formation of the Adenylate Cyclase Toxin (CyaA) of Bordetella pertussis in Lipid Bilayer Membranes.
Knapp, O, Benz, R
Toxins. 2020;(3)
Abstract
The Gram-negative bacterium Bordetella pertussis is the cause of whooping cough. One of its pathogenicity factors is the adenylate cyclase toxin (CyaA) secreted by a Type I export system. The 1706 amino acid long CyaA (177 kDa) belongs to the continuously increasing family of repeat in toxin (RTX) toxins because it contains in its C-terminal half a high number of nine-residue tandem repeats. The protein exhibits cytotoxic and hemolytic activities that target primarily myeloid phagocytic cells expressing the αMβ2 integrin receptor (CD11b/CD18). CyaA represents an exception among RTX cytolysins because the first 400 amino acids from its N-terminal end possess a calmodulin-activated adenylate cyclase (AC) activity. The entry of the AC into target cells is not dependent on the receptor-mediated endocytosis pathway and penetrates directly across the cytoplasmic membrane of a variety of epithelial and immune effector cells. The hemolytic activity of CyaA is rather low, which may have to do with its rather low induced permeability change of target cells and its low conductance in lipid bilayer membranes. CyaA forms highly cation-selective channels in lipid bilayers that show a strong dependence on aqueous pH. The pore-forming activity of CyaA but not its single channel conductance is highly dependent on Ca2+ concentration with a half saturation constant of about 2 to 4 mM.
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5.
Lipid composition of the cancer cell membrane.
Szlasa, W, Zendran, I, Zalesińska, A, Tarek, M, Kulbacka, J
Journal of bioenergetics and biomembranes. 2020;(5):321-342
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Abstract
Cancer cell possesses numerous adaptations to resist the immune system response and chemotherapy. One of the most significant properties of the neoplastic cells is the altered lipid metabolism, and consequently, the abnormal cell membrane composition. Like in the case of phosphatidylcholine, these changes result in the modulation of certain enzymes and accumulation of energetic material, which could be used for a higher proliferation rate. The changes are so prominent, that some lipids, such as phosphatidylserines, could even be considered as the cancer biomarkers. Additionally, some changes of biophysical properties of cell membranes lead to the higher resistance to chemotherapy, and finally to the disturbances in signalling pathways. Namely, the increased levels of certain lipids, like for instance phosphatidylserine, lead to the attenuation of the immune system response. Also, changes in lipid saturation prevent the cells from demanding conditions of the microenvironment. Particularly interesting is the significance of cell membrane cholesterol content in the modulation of metastasis. This review paper discusses the roles of each lipid type in cancer physiology. The review combined theoretical data with clinical studies to show novel therapeutic options concerning the modulation of cell membranes in oncology.
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Dynamic oligomerization of hRAGE's transmembrane and cytoplasmic domains within SDS micelles.
Zamoon, J, Madhu, D, Ahmed, I
International journal of biological macromolecules. 2019;:10-18
Abstract
The human Receptor for Advanced Glycation End Products (hRAGE) is a pattern recognition receptor implicated in inflammation and adhesion. It is involved in both innate and adaptive immunity. Its aberrant signaling is tied to the pathogenesis of diabetic complications, neurodegenerative disorders, and chronic inflammatory responses. Previous structural studies have focused on its extracellular domains with their canonical constant and variable Ig folds, and to a much lesser extent, the intrinsically disorder cytoplasmic domain. No experimental data are reported on the transmembrane domain, which is integral to signaling. We have constructed, expressed and purified the transmembrane domain attached to the cytoplasmic domain of hRAGE in E. coli. Multiple self-associated forms of these domains were observed in vitro. This pattern of mixed oligomers resembled previously reported in vivo forms of the complete receptor. The self-association of these two domains was further characterized using: SDS-PAGE, intrinsic tryptophan fluorescence and heteronuclear NMR spectroscopy. NMR conditions were assessed across time and temperature within micelles. Our data show that the transmembrane and cytoplasmic domains of hRAGE undergo dynamic oligomerizations that can occur in the absence of its extracellular domains or ligand binding. And, such associations are only partially disrupted even with prolonged incubation in strong detergents.