STRUCTURE AND MECHANISTIC STUDIES OF HUMAN FE-S CLUSTER BIOSYNTHESIS

Stanford University, Stanford CA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Friedreich?s ataxia is the most common inherited ataxia and results from the loss of function for the protein frataxin. Frataxin has been implicated in iron homeostasis and, particularly, in iron-sulfur protein biosynthesis. Frataxin specifically interacts with the scaffold protein IscU and delivers iron for iron-sulfur cluster assembly. Although the structure of human frataxin is known, the frataxin iron binding site, the structure of human IscU, and details for the frataxin:IscU complex remain elusive. In addition, clinical mutants of human frataxin have been identified (such as D122Y, G130V, I154F, W155R) but not structurally or functionally characterized. The objectives of this proposal are to determine crystallographic structures of (i) human frataxin with iron;(ii) clinical mutants of frataxin;(iii) human IscU;and (iv) the frataxin:IscU complex.