scholarly journals Gating and Regulatory Mechanisms of TMEM16 Ion Channels and Scramblases

2021 ◽  
Vol 12 ◽  
Author(s):  
Son C. Le ◽  
Pengfei Liang ◽  
Augustus J. Lowry ◽  
Huanghe Yang
Keyword(s):  
Ion Channels ◽  
Molecular Mechanisms ◽  
Transmembrane Protein ◽  
Structural Features ◽  
Regulatory Mechanisms ◽  
Membrane Bilayer ◽  
Flip Flop ◽  
The Past ◽  
Activation Gating ◽  
Health And Disease

The transmembrane protein 16 (TMEM16) family consists of Ca2+-activated ion channels and Ca2+-activated phospholipid scramblases (CaPLSases) that passively flip-flop phospholipids between the two leaflets of the membrane bilayer. Owing to their diverse functions, TMEM16 proteins have been implicated in various human diseases, including asthma, cancer, bleeding disorders, muscular dystrophy, arthritis, epilepsy, dystonia, ataxia, and viral infection. To understand TMEM16 proteins in health and disease, it is critical to decipher their molecular mechanisms of activation gating and regulation. Structural, biophysical, and computational characterizations over the past decade have greatly advanced the molecular understanding of TMEM16 proteins. In this review, we summarize major structural features of the TMEM16 proteins with a focus on regulatory mechanisms and gating.

scholarly journals DNA Methylation Profiles of Tph1A and BDNF in Gut and Brain of L. Rhamnosus-Treated Zebrafish

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 142
Author(s):  
Mariella Cuomo ◽  
Luca Borrelli ◽  
Rosa Della Monica ◽  
Lorena Coretti ◽  
Giulia De Riso ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanisms ◽  
The Past ◽  
Targeted Analysis ◽  
Lack Of Information ◽  
High Resolution Power ◽  
Resolution Level ◽  
Health And Disease ◽  
High Doses ◽  
The Brain

The bidirectional microbiota–gut–brain axis has raised increasing interest over the past years in the context of health and disease, but there is a lack of information on molecular mechanisms underlying this connection. We hypothesized that change in microbiota composition may affect brain epigenetics leading to long-lasting effects on specific brain gene regulation. To test this hypothesis, we used Zebrafish (Danio Rerio) as a model system. As previously shown, treatment with high doses of probiotics can modulate behavior in Zebrafish, causing significant changes in the expression of some brain-relevant genes, such as BDNF and Tph1A. Using an ultra-deep targeted analysis, we investigated the methylation state of the BDNF and Tph1A promoter region in the brain and gut of probiotic-treated and untreated Zebrafishes. Thanks to the high resolution power of our analysis, we evaluated cell-to-cell methylation differences. At this resolution level, we found slight DNA methylation changes in probiotic-treated samples, likely related to a subgroup of brain and gut cells, and that specific DNA methylation signatures significantly correlated with specific behavioral scores.

scholarly journals Unique structural features of the mitochondrial AAA+ protease AFG3L2 reveal the molecular basis for activity in health and disease

2019 ◽  
Author(s):  
Cristina Puchades ◽  
Bojian Ding ◽  
Albert Song ◽  
R. Luke Wiseman ◽  
Gabriel C. Lander ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Molecular Basis ◽  
Molecular Mechanisms ◽  
Structural Data ◽  
Structural Features ◽  
Genetic Mutations ◽  
Biological Functions ◽  
Catalytic Core ◽  
Structural Framework ◽  
Health And Disease

AbstractMitochondrial AAA+ quality control proteases regulate diverse aspects of mitochondrial biology through specialized protein degradation, but the underlying molecular mechanisms that define the diverse activities of these enzymes remain poorly defined. The mitochondrial AAA+ protease AFG3L2 is of particular interest, as genetic mutations localized throughout AFG3L2 are linked to diverse neurodegenerative disorders. However, a lack of structural data has limited our understanding of how mutations impact enzymatic activity. Here, we used cryo-EM to determine a substrate-bound structure of the catalytic core of human AFG3L2. This structure identifies multiple specialized structural features within AFG3L2 that integrate with conserved structural motifs required for hand-over-hand ATP-dependent substrate translocation to engage, unfold and degrade targeted proteins. Mapping disease-relevant AFG3L2 mutations onto our structure demonstrates that many of these mutations localize to these unique structural features of AFG3L2 and distinctly influence its activity and stability. Our results provide a molecular basis for neurological phenotypes associated with different AFG3L2 mutations, and establish a structural framework to understand how different members of the AAA+ superfamily achieve specialized, diverse biological functions.

scholarly journals From Genes to Transcripts, a Tightly Regulated Journey in Plasmodium

2020 ◽  
Vol 10 ◽  
Author(s):  
Thomas Hollin ◽  
Karine G. Le Roch
Keyword(s):  
Life Cycle ◽  
Malaria Parasite ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Regulatory Mechanisms ◽  
Tight Control ◽  
Control Of Gene Expression ◽  
Human Malaria Parasite ◽  
Stage Conversion ◽  
The Past

Over the past decade, we have witnessed significant progresses in understanding gene regulation in Apicomplexa including the human malaria parasite, Plasmodium falciparum. This parasite possesses the ability to convert in multiple stages in various hosts, cell types, and environments. Recent findings indicate that P. falciparum is talented at using efficient and complementary molecular mechanisms to ensure a tight control of gene expression at each stage of its life cycle. Here, we review the current understanding on the contribution of the epigenome, atypical transcription factors, and chromatin organization to regulate stage conversion in P. falciparum. The adjustment of these regulatory mechanisms occurring during the progression of the life cycle will be extensively discussed.

Contributions of Bile Acids to Gastrointestinal Physiology as Receptor Agonists and Modifiers of Ion Channels

2021 ◽  
Author(s):  
Stephen Joseph Keely ◽  
Andreacarola Urso ◽  
Alexandr V Ilyaskin ◽  
Christoph Korbmacher ◽  
Nigel W Bunnett ◽  
...  
Keyword(s):  
Ion Channels ◽  
Bile Acids ◽  
Intestinal Motility ◽  
Molecular Mechanisms ◽  
Epithelial Transport ◽  
Therapeutic Potential ◽  
Gastrointestinal Diseases ◽  
Gastrointestinal Physiology ◽  
The Past ◽  
Current Review

BAs are known to be important regulators of intestinal motility and epithelial fluid and electrolyte transport. Over the past two decades, significant advances in identifying and characterizing the receptors, transporters, and ion channels targeted by bile acids (BAs) has led to exciting new insights into the molecular mechanisms involved in these processes. Our appreciation of BAs, their receptors and BA-modulated ion channels as potential targets for the development of new approaches to treat intestinal motility and transport disorders is increasing. In the current review, we aim to summarize recent advances in our knowledge of the different BA receptors and BA-modulated ion channels present in the gastrointestinal system. We discuss how they regulate motility and epithelial transport, their roles in pathogenesis and their therapeutic potential in a range of gastrointestinal diseases.

Mechanosensitive Ion Channels: Structural Features Relevant to Mechanotransduction Mechanisms

2020 ◽  
Vol 43 (1) ◽  
pp. 207-229 ◽  
Author(s):  
Peng Jin ◽  
Lily Yeh Jan ◽  
Yuh-Nung Jan
Keyword(s):  
Ion Channels ◽  
Structural Features ◽  
Mechanical Force ◽  
Mechanosensitive Channels ◽  
Mechanosensitive Ion Channels ◽  
The Past ◽  
Physiological Processes ◽  
Structural Characterizations

Activation of mechanosensitive ion channels underlies a variety of fundamental physiological processes that require sensation of mechanical force. Different mechanosensitive channels adapt distinctive structures and mechanotransduction mechanisms to fit their biological roles. How mechanosensitive channels work, especially in animals, has been extensively studied in the past decade. Here we review key findings in the functional and structural characterizations of these channels and highlight the structural features relevant to the mechanotransduction mechanism of each specific channel.

scholarly journals Autophagy: Eat Yourself to Live

JMS SKIMS ◽  
2016 ◽  
Vol 19 (2) ◽  
pp. 46
Author(s):  
Zafar Amin Shah
Keyword(s):  
Metabolic Process ◽  
Regulatory Mechanisms ◽  
Kidney Cells ◽  
Newborn Mouse ◽  
The Past ◽  
School Of Medicine ◽  
Health And Disease ◽  
Membrane Bound ◽  
Washington University ◽  
First Descriptions

Autophagy is a metabolic process of consumption of the body's own tissues occurring in starvation and certain diseases. The field of autophagy has grown enormously over the past 10-15 years, with rapid advances in our understanding of the regulatory mechanisms that control autophagy pathways in mammalian systems. It has also improved our understanding of the physiological influences of autophagy in health and disease. It all started in the mid1950s when Sam Clark Jr. of the School of Medicine at Washington University in St. Louis looked through his electron microscope at newborn mouse kidneys and used the term cytolysome for the membrane-bound structures within the cytoplasm of the kidney cells. He and his colleague Edward Essner wrote in 1962 that “Within these cytolysomes remarkable events are in progress”, “Cytoplasm has somehow found its way inside the droplets and is apparently in the process of digestion.” These were the first descriptions of what is known today as macro autophagy and now referred to as autophagy. JMS 2016; 19(2):46

Study of the Molecular Architecture of Keratin Filaments by Electron Microscopy

1982 ◽  
Vol 40 ◽  
pp. 118-119
Author(s):  
U. Aebi ◽  
P. Rew ◽  
T.-T. Sun
Keyword(s):  
Electron Microscopy ◽  
Structural Organization ◽  
Cell Types ◽  
Structural Features ◽  
Molecular Architecture ◽  
The Past ◽  
Keratin Filaments ◽  
Different Types ◽  
10 Nm Filaments ◽  
Different Cell Types

Various types of intermediate-sized (10-nm) filaments have been found and described in many different cell types during the past few years. Despite the differences in the chemical composition among the different types of filaments, they all yield common structural features: they are usually up to several microns long and have a diameter of 7 to 10 nm; there is evidence that they are made of several 2 to 3.5 nm wide protofilaments which are helically wound around each other; the secondary structure of the polypeptides constituting the filaments is rich in ∞-helix. However a detailed description of their structural organization is lacking to date.

Astrocytes in health and disease

2007 ◽  
Vol 148 (15) ◽  
pp. 697-702 ◽  
Author(s):  
Marianna Murányi ◽  
Zsombor Lacza
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Free Radicals ◽  
Molecular Mechanisms ◽  
Neuronal Dysfunction ◽  
Supporting Cells ◽  
Neuronal Synapses ◽  
Health And Disease ◽  
Novel Targets ◽  
Therapeutic Tools

It is now known that astrocytes are not merely supporting cells but they also play an important role in neuronal funcions. Astrocytes tightly ensheat neuronal synapses and regulate the excitation of neurons by uptaking neurotransmitters; reglulate the cerebral blood flow, cerebral fluid volume and extracellular concentrations of ions. They also supply fuel in the form of lactate and provide free radical scavangers such as glutathione for active neurons. These facts indicate that impaired function of astrocytes may lead to neuronal dysfunction. After brain injury (stroke, trauma or tumors) astrocytes are swollen and release active molecules such as glutamate or free radicals resulting in neuronal dysfunction. Thus, investigation of the molecular mechanisms of astrocyte function may reveal novel targets for the development of therapeutic tools in neuronal diseases.

Thermodynamics of the interaction between the spike protein of severe acute respiratory syndrome- coronavirus-2 and the receptor of human angiotensin converting enzyme 2. Effects of possible ligands

2020 ◽  
Author(s):  
Cristina Garcia-Iriepa ◽  
Cecilia Hognon ◽  
Antonio Francés-Monerris ◽  
Isabel Iriepa ◽  
Tom Miclot ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Molecular Mechanisms ◽  
Molecular Design ◽  
Binding Free Energy ◽  
Transmembrane Protein ◽  
Spike Protein ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Rational Molecular Design ◽  
Rational Evaluation

<div><p>Since the end of 2019, the coronavirus SARS-CoV-2 has caused more than 180,000 deaths all over the world, still lacking a medical treatment despite the concerns of the whole scientific community. Human Angiotensin-Converting Enzyme 2 (ACE2) was recently recognized as the transmembrane protein serving as SARS-CoV-2 entry point into cells, thus constituting the first biomolecular event leading to COVID-19 disease. Here, by means of a state-of-the-art computational approach, we propose a rational evaluation of the molecular mechanisms behind the formation of the complex and of the effects of possible ligands. Moreover, binding free energy between ACE2 and the active Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein is evaluated quantitatively, assessing the molecular mechanisms at the basis of the recognition and the ligand-induced decreased affinity. These results boost the knowledge on the molecular grounds of the SARS-CoV-2 infection and allow to suggest rationales useful for the subsequent rational molecular design to treat severe COVID-19 cases.</p></div>

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