Abstract

Copper and zinc containing superoxide dismutase (SOD1) plays a critical role in anti-oxidant defense, yet mutations in SOD1 can lead to amyotrophic lateral sclerosis (ALS), or Lou Gehrigs disease, through a toxic gain of function. The underlying mechanism remains unclear, but an emerging theme involves SOD1 misfolding and formation of toxic SOD1 aggregates. A hypothesis of this research is that the fate of ALS mutant SOD1 is governed by intracellular factors that control post-translational modification of the polypeptide. We have identified a number of such factors, including the CCS copper chaperone, a CCS-independent pathway for activating SOD1, and cytosolic glutaredoxins that help reduce the SOD1 disulfide. Precisely how these factors impact on SOD1 in vivo will be addressed in two Aims of the current proposal:
Aim1 -To understand the pathways for activating human SOD1 with copper: A combination of genetics, biochemistry and structural analyses will explore how human SOD1 discerns between two pathways for acquiring copper and how CCS may uniquely promote SOD1 folding through proline isomerization.
Aim2 -To understand the impact of SOD1 interacting factors on the stability and aggregation of SOD1: Molecular genetic studies in yeast and tissue culture will dissect the opposing roles of the copper activation pathways versus the disulfide reduction pathways in the folding and aggregation of ALS mutant SOD1. In a separate but related line of research, this proposal will also address an unprecedented role for CCS in chromatin silencing:
Aim 3 -To understand the dual roles of CCS in SOD1 activation and chromatin silencing. Yeast genetics and biochemistry will address how CCS can promote both SOD1 activation and chromatin silencing through a possible mechanism involving the anti-aging factor SIR2. Together, these studies in both yeast and mammalian cells promise to shed new light into the biology of SOD1 and its metallochaperone CCS with important implications to disease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM050016-17
Application #
7664264
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Anderson, Vernon
Project Start
1993-08-01
Project End
2010-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
17
Fiscal Year
2009
Total Cost
$326,554
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Robinett, Natalie G; Peterson, Ryan L; Culotta, Valeria C (2018) Eukaryotic copper-only superoxide dismutases (SODs): A new class of SOD enzymes and SOD-like protein domains. J Biol Chem 293:4636-4643
Broxton, Chynna N; Culotta, Valeria C (2016) SOD Enzymes and Microbial Pathogens: Surviving the Oxidative Storm of Infection. PLoS Pathog 12:e1005295
Besold, Angelique N; Culbertson, Edward M; Culotta, Valeria C (2016) The Yin and Yang of copper during infection. J Biol Inorg Chem 21:137-44
Baron, J Allen; Chen, Janice S; Culotta, Valeria C (2015) Cu/Zn superoxide dismutase and the proton ATPase Pma1p of Saccharomyces cerevisiae. Biochem Biophys Res Commun 462:251-6
Li, Cissy X; Gleason, Julie E; Zhang, Sean X et al. (2015) Candida albicans adapts to host copper during infection by swapping metal cofactors for superoxide dismutase. Proc Natl Acad Sci U S A 112:E5336-42
Gleason, Julie E; Galaleldeen, Ahmad; Peterson, Ryan L et al. (2014) Candida albicans SOD5 represents the prototype of an unprecedented class of Cu-only superoxide dismutases required for pathogen defense. Proc Natl Acad Sci U S A 111:5866-71
Gleason, Julie E; Li, Cissy X; Odeh, Hana M et al. (2014) Species-specific activation of Cu/Zn SOD by its CCS copper chaperone in the pathogenic yeast Candida albicans. J Biol Inorg Chem 19:595-603
Baron, J Allen; Laws, Kaitlin M; Chen, Janice S et al. (2013) Superoxide triggers an acid burst in Saccharomyces cerevisiae to condition the environment of glucose-starved cells. J Biol Chem 288:4557-66
Culotta, Valeria C; Daly, Michael J (2013) Manganese complexes: diverse metabolic routes to oxidative stress resistance in prokaryotes and yeast. Antioxid Redox Signal 19:933-44
Aguirre, J Dafhne; Clark, Hillary M; McIlvin, Matthew et al. (2013) A manganese-rich environment supports superoxide dismutase activity in a Lyme disease pathogen, Borrelia burgdorferi. J Biol Chem 288:8468-78

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