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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • Andreas Hornberg
  • Derek Logan
  • Stefan L. Marklund
  • Mikael Oliveberg
Enheter & grupper
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Biologiska vetenskaper

Nyckelord

Originalspråkengelska
Sidor (från-till)333-342
TidskriftJournal of Molecular Biology
Volym365
Utgåva nummer2
StatusPublished - 2007
PublikationskategoriForskning
Peer review utfördJa