The coupling between disulphide status, metallation and dimer interface strength in Cu/Zn superoxide dismutase

Andreas Hornberg, Derek Logan, Stefan L. Marklund, Mikael Oliveberg

Research output: Contribution to journalArticlepeer-review

Abstract

The gain of neurotoxic function in amyotrophic lateral sclerosis (ALS) has been linked to misfolding of the homodimeric enzyme Cu/Zn superoxide dismutase (SOD). Here, we present the crystal structure of fully cysteine-depleted human SOD (SOD (CallA)), representing a reduced, marginally stable intermediate on the folding pathway in vivo that has also been implicated as neurotoxic precursor state. A hallmark of this species is that it fails to dimerise and becomes trapped as a monomer in the absence of the active-site metals. The crystallographic data show that removal of the C57-C146 disulphide bond sets free the interface loop IV in the apo protein, whereas the same loop remains unaffected in the holo protein. Thus, the low dimerisation propensity of disulphide-reduced apoSOD seems to be of entropic origin due to increased loop flexibility in the monomeric state: in the disulphide-reduced holo protein this gain in configurational entropy upon splitting of the dimer interface is reduced by the metal coordination.
Original languageEnglish
Pages (from-to)333-342
JournalJournal of Molecular Biology
Volume365
Issue number2
DOIs
Publication statusPublished - 2007

Subject classification (UKÄ)

  • Biological Sciences

Free keywords

  • loop entropy
  • dimerisation
  • disulphide bond
  • ALS
  • protein folding

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