MRC National Institute for Medical Research, London
Science for Health
Frataxin is an important regulator of iron metabolism
20 October 2010
Friedreich’s ataxia is a hereditary neurodegenerative disease, currently incurable, that impairs muscular movement and eventually leads to death. The FRDA gene was first identified in 1996 and found to be linked to the disease. Its gene product, frataxin, is an essential iron binding protein which is highly conserved in most organisms from bacteria to humans. Reduced expression levels of this protein are sufficient to induce Friedreich’s ataxia (FRDA), a relentless and currently incurable neurodegenerative disease. Absence of frataxin in knock-out mice is also embryonic lethal.
Frataxin (and its bacterial ortholog, CyaY) has been implicated in one of the most important iron-related metabolic pathways and has interactions with the highly conserved iron-sulfur-cluster (Isc) of proteins, also called the Nfs1/Isu complex (or IscS/IscU in bacteria). To understand frataxin's function it is crucial to discover which of the Isc components frataxin binds to.
Annalisa Pastore (pictured) and her group in NIMR’s Division of Molecular Structure have dissected the interactions of the Isc components by examing the structure of their complexes using a technique called small angle X-ray scattering (SAXS). This technique is able to provide the overall shape of even large molecular assemblies. They validated the surfaces of interaction by mapping them directly, using NMR chemical shift perturbation techniques and mutagenesis studies.
The research has modelled the structure of the ternary complex (IscS/IscU/CyaY) and quantified the role of each component in stabilizing the others. This has shown for the first time that frataxin is part of a complex network of multiple interactions between cell components and is directly implicated in the regulation of the iron metabolism. The protein is a regulator of the metabolic pathway necessary to store iron in the organism. They also suggest a role for frataxin as the regulator of a complex network of multiple and competing interactions, whose nature is just starting to be understood.
It is impossible to establish a rational cure for Friedreich's ataxia without understanding its causes. We have been working on understanding the disease since the FRDA gene was found in 1996. Our work provides a new paradigm for understanding the function of frataxin, the protein responsible for the neurodegenerative and incurable Friedreich's ataxia. These findings have direct implications in the development of therapeutic interventions to cure Friedreich's ataxia patients. It also sheds light on one of the most important and yet poorly understood metabolic pathway, that determines how iron, which is essential for life, is stored in the living cell.
Annalisa Pastore
Structure of the ternary complex CyaY/IscS/IscU
A) Surface representation
of the model obtained by combining the SAXS and NMR information showing in blue
and cyan the two IscS protomers, in red and orange red IscU and in gold and yellow
CyaY.
B) Surface representation in the same orientation as in A) of the IscS complex
(blue and light blue) with TusA20 (different gradations of green, 3LVJ).
Original article
Structural bases for the interaction of frataxin with the central components of iron sulfur cluster assembly
Filippo Prischi, Petr V. Konarev, Clara Iannuzzi, Chiara Pastore, Salvatore Adinolfi, Stephen R. Martin, Dmitri I. Svergun, Annalisa Pastore (2010)
Nature Communications, 1:95. Fulltext
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