Essential yet toxic metal on the move
Manganese – an element in the Earth’s crust that is used in industrial processes – is one of seven essential dietary metals for animals. But at high concentrations, manganese can be toxic, especially to the brain, where it causes a syndrome called “manganism” that closely resembles idiopathic Parkinson’s disease.
To study mechanisms of manganese toxicity, Michael Aschner, Ph.D., and colleagues have characterized manganese transport in the worm C. elegans. In the November issue of PLoS ONE, they report the identification of three metal transporters in C. elegans – SMF-1, SMF-2, and SMF-3 – that are related to DMT1, the major manganese transporter in mammals. The study identified SMF-3 as the main manganese uptake transporter in the worm and showed that SMF-2 was involved in metal content regulation. The findings suggest an evolutionarily conserved role for DMT1-related proteins in the regulation of manganese uptake, and they support the use of C. elegans as an in vivo model for investigating metal toxicity and related neurodegenerative disorders.
— Leigh MacMillan
Phosphorylation around the clock
Circadian clocks are biological timekeepers, regulating the metabolic, physiological and behavioral aspects of life on a nearly perfect 24-hour cycle. Martin Egli, Ph.D., and colleagues are using the circadian clock of blue-green algae (cyanobacteria) – which can be reconstituted in vitro from the three proteins KaiA, KaiB and KaiC – to understand the clock mechanisms. KaiC, the core clock component, contains two phosphorylation sites (P-sites) that become phosphorylated and dephosphorylated in a strict order over a 24-hour cycle.
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To understand the mechanisms underlying this phosphorylation sequence, Egli and colleagues have determined the structures of a series of KaiC mutants. In the November issue of PLoS ONE, the researchers describe the subtle conformational changes that may help explain the orderly process of phosphorylation and dephosphorylation. They also identify a third potential P-site in KaiC, calling into question the common assumption of two P-sites in this core clock protein. The structures, combined with functional data, shed light on the various enzymatic activities of KaiC and the function of this molecular timekeeper.
— Melissa Marino
Molecular key to leukemia puzzle?
Transforming growth-interacting factor (TGIF), a protein known to repress gene transcription, has been implicated in some cancers including acute myelogenous leukemia (AML). Rizwan Hamid, M.D., Ph.D., and colleagues have found that TGIF levels predict overall survival in this leukemia: AML patients with lower levels of TGIF have a worse prognosis than patients with higher TGIF levels. But TGIF’s role in hematopoiesis (blood cell development) has not yet been defined.
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— Melissa Marino
Abnormal airways in tiny babies
Babies who are born prematurely are at risk for bronchopulmonary dysplasia (BPD) – abnormal lung development that can cause chronic lung disease. While BPD is associated with inflammation, the molecular mechanisms underlying arrested lung development have not been identified.
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In a previous study, Lawrence Prince, M.D., Ph.D., and colleagues showed that disrupting fibronectin (an extracellular matrix protein) in a mouse model of BPD arrested lung airway branching. They now report in the Nov. 15 issue of Developmental Biology that the fibronectin receptor – integrin α8β1 – is decreased in lung tissue in the same mouse model. They verify a role for integrin α8β1 in lung development using α8-knockout mice, and they show in vivo and in vitro that fetal lung cells from the α8-knockout mice fail to form stable adhesions and have increased migration. The findings show that integrin α8β1 is critical for normal lung development and suggest that defects in integrin-matrix interactions could contribute to diseases of abnormal lung development like BPD.
— Leigh MacMillan
We welcome suggestions for research to highlight in Aliquots. The items should be primary research articles (no reviews, editorials or commentaries) published within the last two months in a peer-reviewed journal. Please send the article citation (PDF if available) and any other feedback about the column to: aliquots@vanderbilt.edu.
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