| pubmed-article:20889968 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:20889968 | lifeskim:mentions | umls-concept:C0007634 | lld:lifeskim |
| pubmed-article:20889968 | lifeskim:mentions | umls-concept:C0035820 | lld:lifeskim |
| pubmed-article:20889968 | lifeskim:mentions | umls-concept:C0016719 | lld:lifeskim |
| pubmed-article:20889968 | lifeskim:mentions | umls-concept:C1171362 | lld:lifeskim |
| pubmed-article:20889968 | lifeskim:mentions | umls-concept:C0597298 | lld:lifeskim |
| pubmed-article:20889968 | lifeskim:mentions | umls-concept:C0205307 | lld:lifeskim |
| pubmed-article:20889968 | lifeskim:mentions | umls-concept:C0017262 | lld:lifeskim |
| pubmed-article:20889968 | lifeskim:mentions | umls-concept:C0387678 | lld:lifeskim |
| pubmed-article:20889968 | lifeskim:mentions | umls-concept:C1515670 | lld:lifeskim |
| pubmed-article:20889968 | lifeskim:mentions | umls-concept:C1158193 | lld:lifeskim |
| pubmed-article:20889968 | pubmed:issue | 49 | lld:pubmed |
| pubmed-article:20889968 | pubmed:dateCreated | 2010-11-29 | lld:pubmed |
| pubmed-article:20889968 | pubmed:abstractText | Friedreich ataxia (FRDA) is an autosomal recessive degenerative disease caused by insufficient expression of frataxin (FXN), a mitochondrial iron-binding protein required for Fe-S cluster assembly. The development of treatments to increase FXN levels in FRDA requires elucidation of the steps involved in the biogenesis of functional FXN. The FXN mRNA is translated to a precursor polypeptide that is transported to the mitochondrial matrix and processed to at least two forms, FXN(42-210) and FXN(81-210). Previous reports suggested that FXN(42-210) is a transient processing intermediate, whereas FXN(81-210) represents the mature protein. However, we find that both FXN(42-210) and FXN(81-210) are present in control cell lines and tissues at steady-state, and that FXN(42-210) is consistently more depleted than FXN(81-210) in samples from FRDA patients. Moreover, FXN(42-210) and FXN(81-210) have strikingly different biochemical properties. A shorter N terminus correlates with monomeric configuration, labile iron binding, and dynamic contacts with components of the Fe-S cluster biosynthetic machinery, i.e. the sulfur donor complex NFS1·ISD11 and the scaffold ISCU. Conversely, a longer N terminus correlates with the ability to oligomerize, store iron, and form stable contacts with NFS1·ISD11 and ISCU. Monomeric FXN(81-210) donates Fe(2+) for Fe-S cluster assembly on ISCU, whereas oligomeric FXN(42-210) donates either Fe(2+) or Fe(3+). These functionally distinct FXN isoforms seem capable to ensure incremental rates of Fe-S cluster synthesis from different mitochondrial iron pools. We suggest that the levels of both isoforms are relevant to FRDA pathophysiology and that the FXN(81-210)/FXN(42-210) molar ratio should provide a useful parameter to optimize FXN augmentation and replacement therapies. | lld:pubmed |
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| pubmed-article:20889968 | pubmed:language | eng | lld:pubmed |
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| pubmed-article:20889968 | pubmed:citationSubset | IM | lld:pubmed |
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| pubmed-article:20889968 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:20889968 | pubmed:month | Dec | lld:pubmed |
| pubmed-article:20889968 | pubmed:issn | 1083-351X | lld:pubmed |
| pubmed-article:20889968 | pubmed:author | pubmed-author:IsayaGraziaG | lld:pubmed |
| pubmed-article:20889968 | pubmed:author | pubmed-author:GakhOleksandr... | lld:pubmed |
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| pubmed-article:20889968 | pubmed:author | pubmed-author:SmithDouglas... | lld:pubmed |
| pubmed-article:20889968 | pubmed:author | pubmed-author:DuncanSamanth... | lld:pubmed |
| pubmed-article:20889968 | pubmed:issnType | Electronic | lld:pubmed |
| pubmed-article:20889968 | pubmed:day | 3 | lld:pubmed |
| pubmed-article:20889968 | pubmed:volume | 285 | lld:pubmed |
| pubmed-article:20889968 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:20889968 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:20889968 | pubmed:pagination | 38486-501 | lld:pubmed |
| pubmed-article:20889968 | pubmed:dateRevised | 2011-4-14 | lld:pubmed |
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| pubmed-article:20889968 | pubmed:year | 2010 | lld:pubmed |
| pubmed-article:20889968 | pubmed:articleTitle | Normal and Friedreich ataxia cells express different isoforms of frataxin with complementary roles in iron-sulfur cluster assembly. | lld:pubmed |
| pubmed-article:20889968 | pubmed:affiliation | Department of Pediatric & Adolescent Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA. | lld:pubmed |
| pubmed-article:20889968 | pubmed:publicationType | Journal Article | lld:pubmed |
| pubmed-article:20889968 | pubmed:publicationType | Research Support, Non-U.S. Gov't | lld:pubmed |
| pubmed-article:20889968 | pubmed:publicationType | Research Support, N.I.H., Extramural | lld:pubmed |
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