The mitochondrial protein frataxin is essential for cellular regulation of iron homeostasis. Although the exact function of frataxin is not yet clear, recent reports indicate the protein binds iron and can act as a mitochondrial iron chaperone to transport Fe(II) to ferrochelatase and ISU proteins within the heme and iron-sulfur cluster biosynthetic pathways, respectively. We have determined the solution structure of apo yeast frataxin to provide a structural basis of how frataxin binds and donates iron to the ferrochelatase. While the protein's α-β-sandwich structural motif is similar to that observed for human and bacterial frataxins, the yeast structure presented in this report includes the full N-terminus observed for the mature processed protein found within the mitochondrion. In addition, NMR spectroscopy was used to identify frataxin amino acids that are perturbed by the presence of iron. Conserved acidic residues in the helix 1-strand 1 protein region undergo amide chemical shift changes in the presence of Fe(II), indicating a possible iron-binding site on frataxin. NMR spectroscopy was further used to identify the intermolecular binding interface between ferrochelatase and frataxin. Ferrochelatase appears to bind to frataxin's helical plane in a manner that includes its iron-binding interface.Frataxin, a mitochondrial protein known to participate in regulating cellular iron homeostasis (1-3), has recently been suggested to play a direct role in producing both heme and Fe-S clusters (4,5). Reduced frataxin levels are the principal cause of the autosomal recessive neurodegenerative disorder Friedreich's ataxia, affecting one in 50 000 humans † This work is supported by the American Heart Association, Midwest Affiliate (Grant 0130527Z to T.L.S.) and by the National Institutes of Health (Grant DK53953 to A.D.). ‡ NMR assignments, atomic coordinates, and chemical shift data for frataxin have been deposited (PDB entry 1XAQ, BMRB entry 11688 6,7). A cellular frataxin deficiency causes mitochondrial iron overload and impairment of both heme and Fe-S cluster biosynthesis (1,2,8). Cellular heme production is accomplished by the enzyme ferrochelatase, which utilizes iron and protoporphyrin as substrates to produce heme, and recent reports indicate frataxin binds to ferrochelatase with a nanomolar binding affinity (5,9). Frataxin has also been shown to donate iron to ferrochelatase for the completion of in vitro heme synthesis (9,10). These results suggest frataxin may act as an iron chaperone to deliver the Fe(II) required to complete cellular heme biosynthesis.Frataxin has been shown to bind iron and partially protect metal against aerobic oxidation, suggesting in vivo protein could deliver the Fe(II) required by frataxin's protein binding partners to complete heme and iron-sulfur cluster biosynthesis (11)(12)(13)(14). The presence of iron can induce aggregation in human and yeast frataxins (12,13); however, this oligomerization is dependent on solution conditions (11,15). Monomeric human and bacterial ...
In this review, we discuss the expression, regulation, downstream mechanisms, and function of stress-induced stress enzymes in mammalian oocytes, peri-implantation embryos, and the stem cells derived from those embryos. Recent reports suggest that stress enzymes mediate developmental functions during early mammalian development, in addition to the homeostatic functions shared with somatic cells. Stress-induced enzymes appear to insure that necessary developmental events occur: many of these events may occur at a slower rate, although some may occur more rapidly. Developmental events induced by stress may be mediated by a single dominant enzyme, but there are examples of responses that require the integration of more than one stress enzyme. The discussion focuses on the consequences of stress as a function of duration and magnitude, and this includes an emerging understanding of the threshold levels of duration and magnitude that lead to pathology. Other topics discussed are the reversibility of the developmental as well as homeostatic consequences of stress, the further problems with readaptation after stress subsides, and the mechanisms and functions of stress enzymes during early mammalian development. The analyses are done with specific concern for their practical impact in assisted reproductive technology (ART) and stem cell technologies.
In Sickle Cell Anemia (SCA) patient blood transfusions are an important part of treatment for stroke and its prevention. However, blood transfusions can also lead to complications such as Reversible Posterior Leukoencephalopathy Syndrome (RPLS). This brief report highlights two cases of SCA who developed such neurological complications after a blood transfusion. RLPS should be considered as the cause of neurologic finding in patients with SCA and hypertension following a blood transfusion.
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