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Insights into SOD1-linked amyotrophic lateral sclerosis from NMR studies of Ni2+- and other metal-ion-substituted wild-type copper–zinc superoxide dismutases

Abstract

The dimeric Cu–Zn superoxide dismutase (SOD1) is a particularly interesting system for biological inorganic chemical studies because substitutions of the native Cu and/or Zn ions by a nonnative metal ion cause minimal structural changes and result in high enzymatic activity for those derivatives with Cu remaining in the Cu site. The pioneering NMR studies of the magnetically coupled derivative Cu2Co2SOD1 by Ivano Bertini and coworkers are of particular importance in this regard. In addition to Co2+, Ni2+ is a versatile metal ion for substitution into SOD1, showing very little disturbance of the structure in Cu2Ni2SOD1 and acting as a very good mimic of the native Cu ion in Ni2Zn2SOD1. The NMR studies presented here were inspired by and are indebted to Ivano Bertini’s paramagnetic NMR pursuits of metalloproteins. We report Ni2+ binding to apo wild-type SOD1 and a time-dependent Ni2+ migration from the Zn site to the Cu site, and the preparation and characterization of Ni2Ni2SOD1, which shows coordination properties similar to those of Cu2Cu2SOD1, namely, an anion-binding property different from that of the wild type and a possibly broken bridging His. Mutations in the human SOD1 gene can cause familial amyotrophic lateral sclerosis (ALS), and mutant SOD1 proteins with significantly altered metal-binding behaviors are implicated in causing the disease. We conclude by discussing the effects of the ALS mutations on the remarkable stabilities and metal-binding properties of wild-type SOD1 proteins and the implications concerning the causes of SOD1-linked ALS.

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Acknowledgments

This research was supported by grants from the National Institutes of Health (R01GM28222 and P01NS049134).

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Correspondence to Li-June Ming or Joan Selverstone Valentine.

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Dedicated to Professor Ivano Bertini for his inspiration, encouragement, and collaboration in our paramagnetic NMR pursuits of superoxide dismutase 1 and other metalloproteins.

Responsible Editors: Lucia Banci and Claudio Luchinat

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Ming, LJ., Valentine, J.S. Insights into SOD1-linked amyotrophic lateral sclerosis from NMR studies of Ni2+- and other metal-ion-substituted wild-type copper–zinc superoxide dismutases. J Biol Inorg Chem 19, 647–657 (2014). https://doi.org/10.1007/s00775-014-1126-5

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  • DOI: https://doi.org/10.1007/s00775-014-1126-5

Keywords

  • Binding affinity
  • Superoxide
  • Nuclear magnetic resonance
  • Protein folding