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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Andreas Hornberg
  • Derek Logan
  • Stefan L. Marklund
  • Mikael Oliveberg
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Biological Sciences

Keywords

  • loop entropy, dimerisation, disulphide bond, ALS, protein folding
Original languageEnglish
Pages (from-to)333-342
JournalJournal of Molecular Biology
Volume365
Issue number2
Publication statusPublished - 2007
Publication categoryResearch
Peer-reviewedYes