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MyBP-C: one protein to govern them all.
Heling, LWHJ, Geeves, MA, Kad, NM
Journal of muscle research and cell motility. 2020;(1):91-101
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Abstract
The heart is an extraordinarily versatile pump, finely tuned to respond to a multitude of demands. Given the heart pumps without rest for decades its efficiency is particularly relevant. Although many proteins in the heart are essential for viability, the non-essential components can attract numerous mutations which can cause disease, possibly through alterations in pumping efficiency. Of these, myosin binding protein C is strongly over-represented with ~ 40% of all known mutations in hypertrophic cardiomyopathy. Therefore, a complete understanding of its molecular function in the cardiac sarcomere is warranted. In this review, we revisit contemporary and classical literature to clarify both the current standing of this fast-moving field and frame future unresolved questions. To date, much effort has been directed at understanding MyBP-C function on either thick or thin filaments. Here we aim to focus questions on how MyBP-C functions at a molecular level in the context of both the thick and thin filaments together. A concept that emerges is MyBP-C acts to govern interactions on two levels; controlling myosin access to the thin filament by sequestration on the thick filament, and controlling the activation state and access of myosin to its binding sites on the thin filament. Such affects are achieved through directed interactions mediated by phosphorylation (of MyBP-C and other sarcomeric components) and calcium.
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Annexin A2 in Inflammation and Host Defense.
Dallacasagrande, V, Hajjar, KA
Cells. 2020;(6)
Abstract
Annexin A2 (AnxA2) is a multifunctional calcium2+ (Ca2+) and phospholipid-binding protein that is expressed in a wide spectrum of cells, including those participating in the inflammatory response. In acute inflammation, the interaction of AnxA2 with actin and adherens junction VE-cadherins underlies its role in regulating vascular integrity. In addition, its contribution to endosomal membrane repair impacts several aspects of inflammatory regulation, including lysosome repair, which regulates inflammasome activation, and autophagosome biogenesis, which is essential for macroautophagy. On the other hand, AnxA2 may be co-opted to promote adhesion, entry, and propagation of bacteria or viruses into host cells. In the later stages of acute inflammation, AnxA2 contributes to the initiation of angiogenesis, which promotes tissue repair, but, when dysregulated, may also accompany chronic inflammation. AnxA2 is overexpressed in malignancies, such as breast cancer and glioblastoma, and likely contributes to cancer progression in the context of an inflammatory microenvironment. We conclude that annexin AnxA2 normally fulfills a spectrum of anti-inflammatory functions in the setting of both acute and chronic inflammation but may contribute to disease states in settings of disordered homeostasis.
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Role of Zinc in Zinc-α2-Glycoprotein Metabolism in Obesity: a Review of Literature.
Severo, JS, Morais, JBS, Beserra, JB, Dos Santos, LR, de Sousa Melo, SR, de Sousa, GS, de Matos Neto, EM, Henriques, GS, do Nascimento Marreiro, D
Biological trace element research. 2020;(1):81-88
Abstract
Excessive adipose tissue promotes the manifestation of endocrine disorders such as reduction of the secretion of zinc-α2-glycoprotein (ZAG), an adipokine with anti-inflammatory and lipid-mobilizing activity. The molecular structure of this adipokine includes binding sites for zinc, a trace element with important antioxidant and immunological proprieties that also participates in energy metabolism and stimulates the function of ZAG. The objective of this review is to highlight current data on the metabolism of ZAG in obesity and the role of zinc in this process. The identified studies show that subjects with obesity have low serum concentrations of zinc and ZAG, as well as low expression of the genes encoding this protein. Thus, zinc appears to be an important regulator of the homeostasis of ZAG in the body; however, alterations in the metabolism of zinc in obesity appear to compromise the functions of ZAG. Therefore, further studies are needed to clarify the relationship between zinc and ZAG metabolism and its repercussions in obesity.
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4.
Lomitapide-a Microsomal Triglyceride Transfer Protein Inhibitor for Homozygous Familial Hypercholesterolemia.
Stefanutti, C
Current atherosclerosis reports. 2020;(8):38
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Abstract
PURPOSE OF REVIEW Homozygous familial hypercholesterolemia (HoFH) is a rare, genetic condition characterized by high levels of Low density lipoprotein cholesterol (LDL-C); overt, early-onset atherosclerotic cardiovascular disease (ASCVD); and premature cardiovascular events and mortality. Lomitapide is a first-in-class microsomal triglyceride transfer protein inhibitor for the treatment of HoFH. This review provides an update on data emerging from real-world studies of lomitapide following on from its pivotal phase 3 clinical trial in HoFH. RECENT FINDINGS Recent registry data have confirmed that HoFH is characterized by delayed diagnosis, with many patients not receiving effective therapy until they are approaching the age when major adverse cardiovascular events may occur. Data from case series of varying sizes, and from a 163-patient registry of HoFH patients receiving lomitapide, have demonstrated that lomitapide doses are lower and adverse events less severe than in the phase 3 study. Lomitapide enables many patients to reach European Atherosclerosis Society LDL-C targets. Some patients are able to reduce frequency of lipoprotein apheresis or, in some cases, stop the procedure altogether-unless there is significant elevation of lipoprotein (a). Modelling analyses based on historical and clinical trial data indicate that lomitapide has the potential to improve cardiovascular outcomes and survival in HoFH. Real-world clinical experience with lomitapide has shown the drug to be effective with manageable, less marked adverse events than in formal clinical studies. Event modelling data suggest a survival benefit with lomitapide in HoFH.
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Novel ASCC1 mutations causing prenatal-onset muscle weakness with arthrogryposis and congenital bone fractures.
Böhm, J, Malfatti, E, Oates, E, Jones, K, Brochier, G, Boland, A, Deleuze, JF, Romero, NB, Laporte, J
Journal of medical genetics. 2019;(9):617-621
Abstract
BACKGROUND The activating signal cointegrator 1 (ASC-1) complex acts as a transcriptional coactivator for a variety of transcription factors and consists of four subunits: ASCC1, ASCC2, ASCC3 and TRIP4. A single homozygous mutation in ASCC1 has recently been reported in two families with a severe muscle and bone disorder. OBJECTIVE We aim to contribute to a better understanding of the ASCC1-related disorder. METHODS Here, we provide a clinical, histological and genetic description of three additional ASCC1 families. RESULTS All patients presented with severe prenatal-onset muscle weakness, neonatal hypotonia and arthrogryposis, and congenital bone fractures. The muscle biopsies from the affected infants revealed intense oxidative rims beneath the sarcolemma and scattered remnants of sarcomeres with enlarged Z-bands, potentially representing a histopathological hallmark of the disorder. Sequencing identified recessive nonsense or frameshift mutations in ASCC1, including two novel mutations. CONCLUSION Overall, this work expands the ASCC1 mutation spectrum, sheds light on the muscle histology of the disorder and emphasises the physiological importance of the ASC-1 complex in fetal muscle and bone development.
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Transition metal transporters in rhizobia: tuning the inorganic micronutrient requirements to different living styles.
Abreu, I, Mihelj, P, Raimunda, D
Metallomics : integrated biometal science. 2019;(4):735-755
Abstract
A group of bacteria known as rhizobia are key players in symbiotic nitrogen fixation (SNF) in partnership with legumes. After a molecular exchange, the bacteria end surrounded by a plant membrane forming symbiosomes, organelle-like structures, where they differentiate to bacteroids and fix nitrogen. This symbiotic process is highly dependent on dynamic nutrient exchanges between the partners. Among these are transition metals (TM) participating as inorganic and organic cofactors of fundamental enzymes. While the understanding of how plant transporters facilitate TMs to the very near environment of the bacteroid is expanding, our knowledge on how bacteroid transporters integrate to TM homeostasis mechanisms in the plant host is still limited. This is significantly relevant considering the low solubility and scarcity of TMs in soils, and the in crescendo gradient of TM bioavailability rhizobia faces during the infection and bacteroid differentiation processes. In the present work, we review the main metal transporter families found in rhizobia, their role in free-living conditions and, when known, in symbiosis. We focus on discussing those transporters which could play a significant role in TM-dependent biochemical and physiological processes in the bacteroid, thus paving the way towards an optimized SNF.
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The SUF system: an ABC ATPase-dependent protein complex with a role in Fe-S cluster biogenesis.
Garcia, PS, Gribaldo, S, Py, B, Barras, F
Research in microbiology. 2019;(8):426-434
Abstract
Iron-sulfur (Fe-S) clusters are considered one of the most ancient and versatile inorganic cofactors present in the three domains of life. Fe-S clusters can act as redox sensors or catalysts and are found to be used by a large number of functional and structurally diverse proteins. Here, we cover current knowledge of the SUF multiprotein machinery that synthesizes and inserts Fe-S clusters into proteins. Specific focus is put on the ABC ATPase SufC, which contributes to building Fe-S clusters, and appeared early on during evolution.
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Transport of Proteins into Mitochondria.
Hansen, KG, Herrmann, JM
The protein journal. 2019;(3):330-342
Abstract
Mitochondria are essential organelles of eukaryotic cells. They consist of hundreds of different proteins that exhibit crucial activities in respiration, catabolic metabolism and the synthesis of amino acids, lipids, heme and iron-sulfur clusters. With the exception of a handful of hydrophobic mitochondrially encoded membrane proteins, all these proteins are synthesized on cytosolic ribosomes, targeted to receptors on the mitochondrial surface, and transported across or inserted into the outer and inner mitochondrial membrane before they are folded and assembled into their final native structure. This review article provides a comprehensive overview of the mechanisms and components of the mitochondrial protein import systems with a particular focus on recent developments in the field.
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Collagen-binding proteins: insights from the Collagen Toolkits.
Farndale, RW
Essays in biochemistry. 2019;(3):337-348
Abstract
The Collagen Toolkits are libraries of 56 and 57 triple-helical synthetic peptides spanning the length of the collagen II and collagen III helices. These have been used in solid-phase binding assays to locate sites where collagen receptors and extracellular matrix components bind to collagens. Truncation and substitution allowed exact binding sites to be identified, and corresponding minimal peptides to be synthesised for use in structural and functional studies. 170 sites where over 30 proteins bind to collagen II have been mapped, providing firm conclusions about the amino acid distribution within such binding sites. Protein binding to collagen II is not random, but displays a periodicity of approximately 28 nm, with several prominent nodes where multiple proteins bind. Notably, the vicinity of the collagenase-cleavage site in Toolkit peptide II-44 is highly promiscuous, binding over 20 different proteins. This may reflect either the diverse chemistry of that locus or its diverse function, together with the interplay between regulatory binding partners. Peptides derived from Toolkit studies have been used to determine atomic level resolution of interactions between collagen and several of its binding partners and are finding practical application in tissue engineering.
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10.
Zinc and Skin Disorders.
Ogawa, Y, Kinoshita, M, Shimada, S, Kawamura, T
Nutrients. 2018;(2)
Abstract
The skin is the third most zinc (Zn)-abundant tissue in the body. The skin consists of the epidermis, dermis, and subcutaneous tissue, and each fraction is composed of various types of cells. Firstly, we review the physiological functions of Zn and Zn transporters in these cells. Several human disorders accompanied with skin manifestations are caused by mutations or dysregulation in Zn transporters; acrodermatitis enteropathica (Zrt-, Irt-like protein (ZIP)4 in the intestinal epithelium and possibly epidermal basal keratinocytes), the spondylocheiro dysplastic form of Ehlers-Danlos syndrome (ZIP13 in the dermal fibroblasts), transient neonatal Zn deficiency (Zn transporter (ZnT)2 in the secretory vesicles of mammary glands), and epidermodysplasia verruciformis (ZnT1 in the epidermal keratinocytes). Additionally, acquired Zn deficiency is deeply involved in the development of some diseases related to nutritional deficiencies (acquired acrodermatitis enteropathica, necrolytic migratory erythema, pellagra, and biotin deficiency), alopecia, and delayed wound healing. Therefore, it is important to associate the existence of mutations or dysregulation in Zn transporters and Zn deficiency with skin manifestations.