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Intracellular Maturation of Acute Phase Proteins
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Erik Fries, E. Mathilda Sjöberg
Many secretory proteins are synthesized as precursors which must be proteolytically cleaved to become biologically active. One example is haptoglobin, which occurs in plasma as an α2β2 tetramer of 90 kDa. The α- and β-chains (of 9 and 35 kDa, respectively) are formed from a 42-kDa precursor which is cleaved in the ER.89 With haptoglobin the only known exception, intracellular proteolytic processing of secretory proteins occurs late during intracellular transport — in the trans-Golgi network and/or secretory vesicles.90-92 The enzyme carrying out this processing specifically cleaves at dibasic sequences, such as those found in, e.g., proalbumin and pro-C4.93-94
Coagulation Theory, Principles, and Concepts
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
The tetramer circulates at plasma concentrations of about 20 μg/mL, with a dimer of the b subunits having a plasma concentration of 10 μg/mL. The tetramer has a molecular weight of 320,000. The subunits are held together by noncovalent bonds. Factor XIII appears to circulate complexed with fibrinogen. Factor XIII is also found in platelets and placenta, but these forms consist only of the a dimers having a molecular weight of 160,000. The active enzymatic site of factor XIII is located in the a subunits.
Regulation of Synthesis of the β & β′ Subunits of RNA Polymerase of Escherichia Coli
Published in James F. Kane, Multifunctional Proteins: Catalytic/Structural and Regulatory, 2019
Rudolph Spangler, Geoffrey Zubay
Early attempts to purify the enzyme led to the isolation of a tetramer containing two α subunits, one β subunit, and one β′ subunit with molecular weights of 44,000, 150,000, and 165,000 dal tons, respectively. This enzyme was highly active in vitro when assayed with nicked template and a mixture of Mg2+ and Mn2+ divalent cations. Enzyme activity was greatly reduced when nicked template was replaced by intact DNA. High activity could be restored in the presence of the 70 kilodalton σ factor, which is now known to be required for correct promoter recognition. This factor dissociates shortly after initiation of transcription, so it is hardly surprising that it was lost in early purification procedures in which the assays for activity were not designed to score for correct initiation. Another small protein factor called co (not to be confused with the Type I topoisomerase of E. coli also called co) co-purifies with the so-called holoenzyme, but no functional activity has been demonstrated for this subunit. Other factors have been described which are believed to be required for the initiation or termination of transcription of certain gene products. The current description of the holoenzyme then is that of a pentamer containing σ, 2α, 1 β, and 1 β′ but not necessarily excluding other more or less firmly bound proteins which may be required in some or all transcriptional events.
Current approaches to evaluate the function of cytotoxic T-cells in non-human primates
Published in Journal of Immunotoxicology, 2023
Cris Kamperschroer, Brendon Frank, Caroline Genell, Hervé Lebrec, Shermaine Mitchell-Ryan, Brigitte Molinier, Courtni Newsome, Marie-Soleil Piche, Daniel Weinstock, Mark Collinge, Wendy Freebern, Daniel Rubio
Tetramer technology allows the identification of CTL that respond to a particular antigen. MHC tetramers are composed of four peptide-MHC Class I complexes linked to a fluorescent molecule. A given MHC tetramer binds only CTL that have T-cell receptors (TCR) specific for the particular peptide-MHC complex. Thus, when a particular tetramer is added to a cell population containing T-cells, that bear TCR specific for the tetramer (e.g. PBMC, spleen cells, or lymph node cells), they become fluorescently labeled. Using flow cytometry, it is then possible to determine the proportion of cells in a population that have TCR specific for a particular antigen by counting the number of tetramer positive cells within a cell population, as well as identifying specific cell populations by cell-specific marker antibodies (Figures 3(a–c)). This sensitive approach can detect antigen-specific T-cells even when their frequency in the CD8+ population is as low as 0.1% (Figure 3). Furthermore, one can directly measure the increase in antigen-specific CD8+ T-cells in response to exposure to pathogens such as viruses or cancer-associated antigens. Therefore, the use of tetramer technology facilitates accurate discrimination of rare specific T-cells. A limitation with tetramer analysis is that it is limited to the species in which the peptide antigen sequence and its MHC-I restriction element have been defined. Thus far, availability of tetramers is generally only for rodents, humans, and monkeys.
Overview of current progress and challenges in diagnosis, and management of pediatric sickle cell disease in Democratic Republic of the Congo
Published in Hematology, 2022
Emmanuel Tebandite Kasai, Jean Pierre Alworong’a Opara, Justin Ntokamunda Kadima, Masendu Kalenga, Salomon Batina Agasa, Roland Marini Djang’eing‘a, François Boemer
Hemoglobinopathy is defined as a blood pathology caused by genetic mutations that lead to qualitative and quantitative changes in structure and quantity of hemoglobin (Hb) chains [1]. To date, over a thousand variants of hemoglobin are described in the HbVar database. Not all these variants are clinically significant [2]. Globally, hemoglobinopathies fall into two main groups, including structural variants of hemoglobin (abnormal hemoglobins) and thalassemia syndromes (α-and β-thalassemia). Hemoglobin is a tetramer made up of two chains of α-globin and two chains of β-globin working together with heme to transport oxygen in the blood [1]. Normal adult hemoglobin (HbA) is referred to as αA2βA2 [1]. Variant hemoglobin is derived from genetic mutations in the structural genes of α-globin (HBA1 or HBA2) or β-globin (HBB) (exons).
Blinded potency comparison of transthyretin kinetic stabilisers by subunit exchange in human plasma
Published in Amyloid, 2021
Luke T. Nelson, Ryan J. Paxman, Jin Xu, Bill Webb, Evan T. Powers, Jeffery W. Kelly
To facilitate TTR tetramer detection in plasma, in the context of thousands of additional proteins and biomolecules, we employed the fluorogenic TTR-modifying small molecule A2 (Figure 1(B)) [39]. Small molecule A2 binds rapidly to natively folded tetrameric TTR, arresting any further subunit exchange and yielding the non-fluorescent TTR•(A2)2 complexes of tetramers 1–5 (Figure 1(B); left panel). Once bound, A2 chemoselectively reacts with two of the four TTR subunits in the TTR tetramer, acylating the Lys-15 ε-amino groups in the thyroxine binding sites, rendering the TTR-(A2 fragment)2 covalent conjugates of tetramers 1–5 fluorescent (Figure 1(B); right panel). Because the N-terminal dual-FLAG tag does not affect the A2 binding site, using the FLAG-tagged TTR allows for equal fluorescence detection of tetramers 1–5. The additional negative charges contributed by each TTR subunit harbouring a dual-FLAG tag (red subunits) in a tetramer allows for ultraperformance liquid chromatography (UPLC) quaternary ammonium anion exchange chromatography separation of tetramers 1–5 in plasma. This enables fluorescence detection-based quantification of TTR-(A2 fragment)2 of tetramers 1–5 (Figure 1(C)) as a function of the subunit exchange period to generate subunit exchange kinetics [29].