Structure and Function of Hepatobiliary ATP Binding Cassette Transporters

Chemical Reviews, Год журнала: 2020, Номер 121(9), С. 5240 - 5288

Опубликована: Ноя. 17, 2020

The liver is beyond any doubt the most important metabolic organ of human body. This function requires an intensive crosstalk within cellular structures, but also with other organs. Membrane transport proteins are therefore upmost importance as they represent sensors and mediators that shuttle signals from outside to inside cells and/or vice versa. In this review, we summarize known literature a clear emphasis on functional structural information ATP binding cassette (ABC) transporters, which expressed in liver. These primary active membrane transporters form one largest families proteins. liver, play essential role for example bile formation or xenobiotic export. Our review provides state art comprehensive summary current knowledge hepatobiliary ABC transporters. Clearly, our has improved breath-taking speed over last few years will expand further. Thus, provide status quo lay foundation new exciting avenues transporter research.

Язык: Английский

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Vascular K _ATP channel structural dynamics reveal regulatory mechanism by Mg-nucleotides

Proceedings of the National Academy of Sciences, Год журнала: 2021, Номер 118(44)

Опубликована: Окт. 28, 2021

Significance Vascular K ATP channels formed by the potassium channel Kir6.1 and its regulatory protein SUR2B maintain blood pressure in physiological range. Overactivity of due to genetic mutations either or causes severe cardiovascular pathologies known as Cantú syndrome. The cryogenic electron microscopy structures vascular reported here show multiple, dynamically related conformations subunit SUR2B. Molecular dynamics simulations reveal negatively charged ED-domain SUR2B, a stretch 15 glutamate (E) aspartate (D) residues not previously resolved, play key MgADP-dependent role mediating interactions at interface between subunits. Our findings provide mechanistic understanding how activity is regulated intracellular MgADP.

Язык: Английский

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The L467F-F508del Complex Allele Hampers Pharmacological Rescue of Mutant CFTR by Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Patients: The Value of the Ex Vivo Nasal Epithelial Model to Address Non-Responders to CFTR-Modulating Drugs

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(6), С. 3175 - 3175

Опубликована: Март 15, 2022

Loss-of-function mutations of the CFTR gene cause cystic fibrosis (CF) through a variety molecular mechanisms involving altered expression, trafficking, and/or activity chloride channel. The most frequent mutation among CF patients, F508del, causes multiple defects that can be, however, overcome by combination three pharmacological agents improve channel trafficking and gating, namely, elexacaftor, tezacaftor, ivacaftor. This study was prompted evidence two compound heterozygous for F508del minimal function variant, who failed to obtain any beneficial effects following treatment with triple drug combination. Functional studies on nasal epithelia generated in vitro from these patients confirmed lack response treatment. Molecular characterization highlighted presence an additional amino acid substitution, L467F, cis demonstrating both were carriers complex allele. biochemical assays heterologous expression systems demonstrated double mutant L467F-F508del has severely reduced activity, negligible rescue modulators. While further are needed investigate actual prevalence allele, our results suggest this allele should be taken into consideration as plausible not responding

Язык: Английский

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SARS-CoV-2 nucleocapsid protein triggers hyperinflammation via protein-protein interaction-mediated intracellular Cl− accumulation in respiratory epithelium

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Июль 27, 2022

Abstract SARS-CoV-2, the culprit pathogen of COVID-19, elicits prominent immune responses and cytokine storms. Intracellular Cl − is a crucial regulator host defense, whereas role signaling pathway in modulating pulmonary inflammation associated with SARS-CoV-2 infection remains unclear. By using human respiratory epithelial cell lines, primary cultured airway cells, murine models viral structural protein stimulation direct challenge, we demonstrated that nucleocapsid (N) could interact Smad3, which downregulated cystic fibrosis transmembrane conductance (CFTR) expression via microRNA-145. The intracellular concentration ([Cl ] i ) was raised, resulting phosphorylation serum glucocorticoid regulated kinase 1 (SGK1) robust inflammatory responses. Inhibition or knockout SGK1 abrogated N protein-elicited inflammation. Moreover, promoted sustained elevation [Cl by depleting cAMP upregulation phosphodiesterase 4 (PDE4). Rolipram, selective PDE4 inhibitor, countered reducing . Our findings suggested acted as pathological second messenger mediating after infection. Targeting might be novel therapeutic strategy for COVID-19.

Язык: Английский

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The Impact of Highly Effective Modulator Therapy on Cystic Fibrosis Microbiology and Inflammation

Clinics in Chest Medicine, Год журнала: 2022, Номер 43(4), С. 647 - 665

Опубликована: Ноя. 4, 2022

Язык: Английский

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