At least 119 mutations in the gene encoding Cu/Zn superoxide dismutase are associated with amyotrophic lateral sclerosis. These SOD1 mutations are believed to result in a toxic property, although the nature of this toxic property has not been identified. In preliminary studies we compared the dynamic properties of thirteen purified SOD1 variant enzymes using hydrogen/deuterium exchange mass spectrometry and identified a shared property, namely structural and dynamic change affecting the electrostatic loop of SOD1. We hypothesize that other modifications of SOD1, including native and non-native post-translational modifications, also perturb the SOD1 electrostatic loop and will test this hypothesis using hydrogen/deuterium exchange mass spectrometry. Although the biological consequences of increased electrostatic loop mobility are not fully understood, this common property would be consistent with hypotheses that SOD1 mutations exert toxicity via aggregation or aberrant association with other cellular constituents.
. The neurodegenerative diseases, including ALS, have proven extraordinarily difficult to treat. This is due in part to the fact that researchers do not know the cause of >90% of ALS. We propose that the aggregation (sticking together) of a protein named SOD1 is involved in ALS progression, and will test if a section of the protein called the electrostatic loop is damaged in ALS.
|Auclair, Jared R; Salisbury, Joseph P; Johnson, Joshua L et al. (2014) Artifacts to avoid while taking advantage of top-down mass spectrometry based detection of protein S-thiolation. Proteomics 14:1152-7|
|Dang, Xibei; Scotcher, Jenna; Wu, Si et al. (2014) The first pilot project of the consortium for top-down proteomics: a status report. Proteomics 14:1130-40|
|Liu, Qian; Easterling, Michael L; Agar, Jeffrey N (2014) Resolving isotopic fine structure to detect and quantify natural abundance- and hydrogen/deuterium exchange-derived isotopomers. Anal Chem 86:820-5|
|Auclair, Jared R; Johnson, Joshua L; Liu, Qian et al. (2013) Post-translational modification by cysteine protects Cu/Zn-superoxide dismutase from oxidative damage. Biochemistry 52:6137-44|
|Auclair, Jared R; Brodkin, Heather R; D'Aquino, J Alejandro et al. (2013) Structural consequences of cysteinylation of Cu/Zn-superoxide dismutase. Biochemistry 52:6145-50|
|Li, Long; Karabacak, N Murat; Cobb, Jennifer S et al. (2010) Memory-efficient calculation of the isotopic mass states of a molecule. Rapid Commun Mass Spectrom 24:2689-96|
|Karabacak, N Murat; Easterling, Michael L; Agar, Nathalie Y R et al. (2010) Transformative effects of higher magnetic field in Fourier transform ion cyclotron resonance mass spectrometry. J Am Soc Mass Spectrom 21:1218-22|
|Cobb, Jennifer S; Easterling, Michael L; Agar, Jeffrey N (2010) Structural characterization of intact proteins is enhanced by prevalent fragmentation pathways rarely observed for peptides. J Am Soc Mass Spectrom 21:949-59|
|Molnar, Kathleen S; Karabacak, N Murat; Johnson, Joshua L et al. (2009) A common property of amyotrophic lateral sclerosis-associated variants: destabilization of the copper/zinc superoxide dismutase electrostatic loop. J Biol Chem 284:30965-73|