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

Hornberg, Andreas; Logan, Derek LU ; Marklund, Stefan L. and Oliveberg, Mikael (2007) In Journal of Molecular Biology 365(2). p.333-342
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
loop entropy, dimerisation, disulphide bond, ALS, protein folding
in
Journal of Molecular Biology
volume
365
issue
2
pages
333 - 342
publisher
Elsevier
external identifiers
  • wos:000243243200006
  • scopus:33751536847
ISSN
1089-8638
DOI
10.1016/j.jmb.2006.09.048
language
English
LU publication?
yes
id
85cbfc6a-844c-4912-bcc2-2de93ac8c889 (old id 679309)
date added to LUP
2007-12-11 14:55:14
date last changed
2017-10-22 04:41:26
@article{85cbfc6a-844c-4912-bcc2-2de93ac8c889,
  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.},
  author       = {Hornberg, Andreas and Logan, Derek and Marklund, Stefan L. and Oliveberg, Mikael},
  issn         = {1089-8638},
  keyword      = {loop entropy,dimerisation,disulphide bond,ALS,protein folding},
  language     = {eng},
  number       = {2},
  pages        = {333--342},
  publisher    = {Elsevier},
  series       = {Journal of Molecular Biology},
  title        = {The coupling between disulphide status, metallation and dimer interface strength in Cu/Zn superoxide dismutase},
  url          = {http://dx.doi.org/10.1016/j.jmb.2006.09.048},
  volume       = {365},
  year         = {2007},
}