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. Nearly all organisms require iron for normal metabolic function. However, due to its reactivity with oxygen, high levels of iron can generate reactive oxygen species which damage DNA, lipids and proteins. In humans, iron regulatory proteins (IRP1 and IRP2) coordinate post-transcriptional regulation of iron homeostasis genes with cellular iron availability. When cellular iron concentration is high, IRP1 acquires an iron sulfur cluster and catalyzes the inter-conversion of citrate and isocitrate. Conversely, when cellular iron concentration is low, IRP1 regulates translation of iron homeostasis genes. These functional changes require IRP1 to undergo structural reorganization whereby two domains either rotate toward each other to form an active site or rotate away from each other to form a RNA binding cleft. The conformation of apo-IRP1 and the structural components of IRP1 that facilitate rigid body domain rotation remain unknown. We hypothesized that the linker and hinge regions determine the global conformation of IRP1 by acting as axes of rigid body domain rotation. To test this hypothesis, mutations designed to prevent structural transitions of IRP1 were implemented in the hinge and linker regions. Preliminary functional analysis indicated that the enzyme activity of hinge mutants decreased by 90% compared to wild type, whereas the RNA binding affinity was similar to wild type. In order to gain further insight toward how these mutations affect global IRP1 conformation, we proposed small angle x-ray scattering experiments to compare radii of gyration, pair distribution functions and low-resolution molecular envelopes of wild type IRP1 to the hinge and linker mutants.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR008630-16
Application #
8361304
Study Section
Special Emphasis Panel (ZRG1-BCMB-E (40))
Project Start
2011-01-01
Project End
2011-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
16
Fiscal Year
2011
Total Cost
$1,975
Indirect Cost
Name
Illinois Institute of Technology
Department
Other Basic Sciences
Type
Schools of Arts and Sciences
DUNS #
042084434
City
Chicago
State
IL
Country
United States
Zip Code
60616
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