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. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the death of motor neurons. Approximately 20% of all inherited cases of ALS are caused by mutations in the gene encoding for Cu, Zn superoxide dismutase (SOD1). One consequence of these mutations is to cause the aggregation of the protein. These mutations occur at over 70 different sites of this 153 amino acid protein, making it difficult to ascertain a common toxic mechanism. SOD1 is a homodimeric enzyme which binds two metal ions per subunit and contains an intramolecular disulfide-bond between C57 and C146. With all of these post-translational modifications intact, the enzyme is highly thermostable, with a melting point over 90 ?C. Recent biophysical analyses have suggested that premature forms of the enzyme, lacking either the metal ions, the disulfide bond or both, may be more likely candidates for aggregation. The disulfide-reduced, metal-free forms of the enzyme have marginal stability, and ALS-variants of the enzyme may even be unfolded at physiological temperatures. In order to determine structural differences in the monomeric forms of SOD1, we plan to study global structural differences between stable monomeric versions of the WT protein and a selected set of ALS variants with small angle x-ray scattering (SAXS). This will include studies of SOD1, with multiple stages of posttranslational modification and under oxidized and reduced conditions and also under various stages of metal loading. The results are expected to have an significant impact on our understanding of the molecular mechanism of disease pathology

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR008630-16
Application #
8361278
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
$17,741
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
Yazdi, Aliakbar Khalili; Vezina, Grant C; Shilton, Brian H (2017) An alternate mode of oligomerization for E. coli SecA. Sci Rep 7:11747
Sullivan, Brendan; Robison, Gregory; Pushkar, Yulia et al. (2017) Copper accumulation in rodent brain astrocytes: A species difference. J Trace Elem Med Biol 39:6-13
Morris, Martha Clare (2016) Nutrition and risk of dementia: overview and methodological issues. Ann N Y Acad Sci 1367:31-7
Robison, Gregory; Sullivan, Brendan; Cannon, Jason R et al. (2015) Identification of dopaminergic neurons of the substantia nigra pars compacta as a target of manganese accumulation. Metallomics 7:748-55
Gelfand, Paul; Smith, Randy J; Stavitski, Eli et al. (2015) Characterization of Protein Structural Changes in Living Cells Using Time-Lapsed FTIR Imaging. Anal Chem 87:6025-31
Liang, Wenguang G; Ren, Min; Zhao, Fan et al. (2015) Structures of human CCL18, CCL3, and CCL4 reveal molecular determinants for quaternary structures and sensitivity to insulin-degrading enzyme. J Mol Biol 427:1345-1358
Zhou, Hao; Li, Shangyang; Badger, John et al. (2015) Modulation of HIV protease flexibility by the T80N mutation. Proteins 83:1929-39
Nobrega, R Paul; Arora, Karunesh; Kathuria, Sagar V et al. (2014) Modulation of frustration in folding by sequence permutation. Proc Natl Acad Sci U S A 111:10562-7
Jiao, Lianying; Ouyang, Songying; Shaw, Neil et al. (2014) Mechanism of the Rpn13-induced activation of Uch37. Protein Cell 5:616-30
Witayavanitkul, Namthip; Ait Mou, Younss; Kuster, Diederik W D et al. (2014) Myocardial infarction-induced N-terminal fragment of cardiac myosin-binding protein C (cMyBP-C) impairs myofilament function in human myocardium. J Biol Chem 289:8818-27

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