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The conformational landscape of human transthyretin revealed by cryo-EM.
Nat Struct Mol Biol
January 2025
Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA, USA.
Transthyretin (TTR) is a natively tetrameric thyroxine transporter in blood and cerebrospinal fluid whose misfolding and aggregation causes TTR amyloidosis. A rational drug design campaign identified the small molecule tafamidis (Vyndamax) as a stabilizer of the native TTR fold, and this aggregation inhibitor is regulatory agency approved for the treatment of TTR amyloidosis. Here we used cryo-EM to investigate the conformational landscape of this 55 kDa tetramer in the absence and presence of one or two ligands, revealing inherent asymmetries in the tetrameric architecture and previously unobserved conformational states.
View Article and Find Full Text PDFProtective role of triiodothyronine in sepsis‑induced cardiomyopathy through phospholamban downregulation.
Int J Mol Med
March 2025
Department of Clinical Laboratory, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing 400014, P.R. China.
Sepsis is often a cause of mortality in patients admitted to the intensive care unit. Notably, the heart is the organ most susceptible to the impact of sepsis and this condition is referred to as sepsis‑induced cardiomyopathy (SIC). Low triiodothyronine (T3) syndrome frequently occurs in patients with sepsis, and the heart is one of the most important target organs for the action of T3.
View Article and Find Full Text PDFIodine Deficiency Exacerbates Thyroidal and Neurological Effects of Developmental Perchlorate Exposure in the Neonatal and Adult Rat.
Toxics
November 2024
National Center for Computational Toxicology, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC 27709, USA.
Thyroid hormones (THs) require iodine for biosynthesis and play critical roles in brain development. Perchlorate is an environmental contaminant that reduces serum THs by blocking the uptake of iodine from the blood to the thyroid gland. Using a pregnant rodent model, we examined the impact of maternal exposure to perchlorate under conditions of dietary iodine deficiency (ID) on the brain and behavior of offspring.
View Article and Find Full Text PDFSpatially dependent tissue distribution of thyroid hormones by plasma thyroid hormone binding proteins.
Pflugers Arch
January 2025
Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA.
Plasma thyroid hormone (TH) binding proteins (THBPs), including thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin (ALB), carry THs to extrathyroidal sites, where THs are unloaded locally and then taken up via membrane transporters into the tissue proper. The respective roles of THBPs in supplying THs for tissue uptake are not completely understood. To investigate this, we developed a spatial human physiologically based kinetic (PBK) model of THs, which produces several novel findings.
View Article and Find Full Text PDFCharacterization of thyroid hormone transport in a human choroid plexus papilloma cell line (HIBCPP) as an in vitro blood-cerebrospinal fluid barrier model.
Mol Cell Endocrinol
February 2025
Amsterdam Institute for Life and Environment (A-Life), Vrije Universiteit Amsterdam (VU), De Boeleni 1085, 1081, HV Amsterdam, the Netherlands.
Adequate levels of thyroid hormones (THs) in the fetal brain are vital for early neurodevelopment. Most of the TH in fetal brain is derived from circulating thyroxine (T4), which gets locally converted into the biologically active triiodothyronine (T3) by deiodinase enzymes. One of the major routes of TH into the brain is through the blood-cerebrospinal fluid barrier (BCSFB).
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