Source:http://linkedlifedata.com/resource/pubmed/id/20889968
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
49
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| pubmed:dateCreated |
2010-11-29
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| 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.
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| pubmed:grant | |
| pubmed:commentsCorrections | |
| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Carbon-Sulfur Lyases,
http://linkedlifedata.com/resource/pubmed/chemical/ISCU protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/ISD11 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Iron,
http://linkedlifedata.com/resource/pubmed/chemical/Iron-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Iron-Regulatory Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Iron-Sulfur Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Mitochondrial Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/NFS1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Isoforms,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Precursors,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/frataxin
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| pubmed:status |
MEDLINE
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| pubmed:month |
Dec
|
| pubmed:issn |
1083-351X
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| pubmed:author | |
| pubmed:issnType |
Electronic
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| pubmed:day |
3
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| pubmed:volume |
285
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
38486-501
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| pubmed:dateRevised |
2011-4-14
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| pubmed:meshHeading |
pubmed-meshheading:20889968-Adolescent,
pubmed-meshheading:20889968-Adult,
pubmed-meshheading:20889968-Carbon-Sulfur Lyases,
pubmed-meshheading:20889968-Cell Line, Transformed,
pubmed-meshheading:20889968-Child,
pubmed-meshheading:20889968-Female,
pubmed-meshheading:20889968-Friedreich Ataxia,
pubmed-meshheading:20889968-Gene Expression Regulation,
pubmed-meshheading:20889968-Humans,
pubmed-meshheading:20889968-Iron,
pubmed-meshheading:20889968-Iron-Binding Proteins,
pubmed-meshheading:20889968-Iron-Regulatory Proteins,
pubmed-meshheading:20889968-Iron-Sulfur Proteins,
pubmed-meshheading:20889968-Male,
pubmed-meshheading:20889968-Mitochondria,
pubmed-meshheading:20889968-Mitochondrial Proteins,
pubmed-meshheading:20889968-Protein Biosynthesis,
pubmed-meshheading:20889968-Protein Isoforms,
pubmed-meshheading:20889968-Protein Precursors,
pubmed-meshheading:20889968-Protein Structure, Tertiary,
pubmed-meshheading:20889968-RNA, Messenger
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| pubmed:year |
2010
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| pubmed:articleTitle |
Normal and Friedreich ataxia cells express different isoforms of frataxin with complementary roles in iron-sulfur cluster assembly.
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| pubmed:affiliation |
Department of Pediatric & Adolescent Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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